* 602858

7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7


Alternative titles; symbols

STEROL DELTA-7-REDUCTASE


HGNC Approved Gene Symbol: DHCR7

Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:71,434,411-71,448,393 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q13.4 Smith-Lemli-Opitz syndrome 270400 AR 3

TEXT

Description

The DHCR7 gene encodes delta-7-sterol reductase (EC 1.3.1.21), the penultimate enzyme of mammalian sterol biosynthesis that converts 7-dehydrocholesterol (7-DHC) to cholesterol. This enzyme removes the C(7-8) double bond introduced by the sterol delta8-delta7 isomerases. In addition, its role in drug-induced malformations is known: inhibitors of the last step of cholesterol biosynthesis such as AY9944 and BM15766 severely impair brain development (Moebius et al., 1998).


Cloning and Expression

Wassif et al. (1998) cloned a cDNA encoding human sterol delta-7-reductase (DHCR7) on the basis of its homology with the sterol delta-7-reductase from Arabidopsis thaliana, and they confirmed the enzymatic function of the human gene product by expression in fibroblasts.

Waterham et al. (1998) identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the EST database with the amino acid sequence of an A. thaliana enzyme. They isolated the remaining 5-prime sequence by 5-prime RACE. By heterologous expression of the cDNA in Saccharomyces cerevisiae, they confirmed that it coded for 7-dehydrocholesterol reductase.

Moebius et al. (1998) cloned the DHCR7 gene. The deduced protein is membrane-bound with a predicted molecular mass of 55 kD and 6 to 9 putative transmembrane segments. The protein is structurally related to plant and yeast sterol reductases. In adults, the ubiquitously transcribed mRNA is most abundant in adrenal gland, liver, testis, and brain. Although important in vertebrates, the enzyme is absent from yeast. Microsomes from Saccharomyces cerevisiae strains heterologously expressing the human cDNA removed the C(7-8) double bond in 7-dehydrocholesterol. The conversion to cholesterol depends on NADPH and is potently inhibited by AY9944, BM15766, and triparanol.


Mapping

Using radiation hybrid mapping, Wassif et al. (1998) mapped the DHCR7 gene to chromosome 11q12-q13. By FISH, Waterham et al. (1998) assigned the DHCR7 gene to 11q13.

Fitzky et al. (1998) characterized the human and mouse DHCR7 genes and assigned them to syntenic regions on 11q13 and 7F5, respectively, by FISH.


Gene Function

Porter et al. (1996) demonstrated that cholesterol is the lipophilic moiety covalently attached to the N-terminal signaling domain of hedgehog proteins (SHH, 600725; IHH, 600726) during autoprocessing and that the C-terminal domain acts as an intramolecular cholesterol transferase. They postulated that some of the effects of perturbed cholesterol biosynthesis on animal development may be due to the fact that cholesterol is used to modify embryonic signaling proteins. They postulated that in SLO syndrome, where cholesterol biosynthesis is defective, there may be defective modification of the hedgehog proteins and perhaps other similarly processed proteins. Porter et al. (1996) postulated further that the spectrum of developmental malformations seen in SLO syndrome may be due to loss of hedgehog protein function.

Using knockout screens in mouse Pfa1 cells, Freitas et al. (2024) identified Dhcr7 as a proferroptotic gene. DHCR7 knockout in the human ferroptosis fibrosarcoma cell line HT1080 led to accumulation of 7-DHC and resistance to ferroptosis, whereas reexpression of DHCR7 abolished 7-DHC concentrations and resensitized cells to ferroptosis. The accumulated 7-DHC in response to DHCR7 knockout functioned as an antiferroptotic metabolite that blocked peroxidation of phospholipids, resulting in truncated phospholipids that prevented execution of ferroptosis to protect cells. In addition, 7-DHC accumulation increased cell fitness and appeared to have in impact on lymphoma growth in a mouse model.

By knockdown screens in HEK293T cells, Li et al. (2024) independently identified DHCR7 as a proferroptotic gene. DHCR7 knockout strongly suppressed ferroptosis, whereas reexpression of DHCR7 reversed ferroptosis resistance in DHCR7-knockout cells. Loss of DHCR7 resulted in accumulation of 7-DHC, which protected the cells from ferroptosis by inhibiting peroxidation of phospholipids. 7-DHC was also involved in regulation of tumor ferroptosis and protection of kidneys from ischemia-reperfusion injury in a mouse model.


Molecular Genetics

Children with the Smith-Lemli-Opitz syndrome (SLOS; 270400) have elevated serum 7-DHC levels and low serum cholesterol levels. In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol delta-7-reductase. Liver microsomes from an SLOS homozygote were shown by Shefer et al. (1995) to have reduced activity of this enzyme.

In 3 unrelated patients with SLOS, Wassif et al. (1998) identified 4 different mutations in the DHCR7 gene (602858.0001-602858.0004). Fitzky et al. (1998) identified mutations in the DHCR7 gene (see, e.g., 602858.0009 and 602858.0011) in patients with SLOS. Waterham et al. (1998) identified homozygous and compound heterozygous mutations in the DHCR7 gene, including the intron 8 splice-site mutation (602858.0001), in patients with SLOS.

De Brasi et al. (1999) stated that 19 mutations in the DHCR7 gene had been described; among these, mutations impairing the activity of the C terminus appeared to be the most severe. They performed mutation analysis of the DHCR7 gene in 9 Italian SLOS patients and identified 3 novel mutations. They found that the T93M mutation (602858.0009) was the most frequent (7 of 18 alleles) in their survey.

In 84 patients with clinically and biochemically characterized SLOS, Witsch-Baumgartner et al. (2000) identified 40 different mutations in the DHCR7 gene. All but 1 of their patients were white, the exception having mostly American Cherokee heritage. On the basis of mutation type and expression studies, the authors grouped the mutations into 4 classes: nonsense and splice site mutations resulting in putative null alleles, missense mutations in the transmembrane domains, mutations in the fourth cytoplasmic loop, and mutations in the C-terminal endoplasmic reticulum (ER) domain. All but 1 of the tested missense mutations reduced protein stability. The mildest clinical phenotypes were associated with transmembrane and C-terminal ER domain mutations, and the most severe types were associated with null alleles and mutations in the fourth cytoplasmic loop. Most homozygotes for null alleles had severe SLOS; 1 patient had a moderate phenotype. Homozygosity for null mutations in the DHCR7 gene appeared compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used. Given that only a few null mutations exist, the authors were surprised to find that 2 of them, IVS8-1G-C (602858.0001) and trp151 to ter (602858.0011), accounted for more than one-third of all mutant alleles. In a note added in proof, Witsch-Baumgartner et al. (2000) stated that 7 additional DHCR7 mutations had been detected in 12 patients with SLOS.

Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for rapid detection of the IVS8-1G-C mutation. This mutation results in abnormal splicing of exon 9 with a 134-bp insertion of intron 8 sequences, a resultant frameshift, and a premature translation stop (602858.0001). The authors identified this mutation in 21 of 33 SLOS propositi (21 of 66 alleles). Since none of their patients was homozygous for this mutation, the authors hypothesized that homozygosity for the mutation may often be prenatally lethal. They also screened unrelated normal individuals for the prevalence of this mutation, including 90 American Caucasians, 120 Finnish Caucasians, 121 Sierra Leone Africans, 95 Han Chinese, and 103 Japanese. One IVS8-1G-C mutation was identified in the American Caucasian population; none was observed in the other populations. Yu et al. (2000) concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S.

Yu et al. (2000) screened an additional 32 patients with SLOS, 28 from the U.S.A. and 4 from Sweden. Twenty missense mutations, 1 nonsense mutation (602858.0012), and 1 splice-site mutation involving the exon 9 acceptor site (IVS8-1G-C; 602858.0001) were detected. All probands were heterozygous for mutations. Three mutations accounted for 54% of those observed in their cohort, the splice acceptor site mutation IVS8-1G-C (22/64 alleles, 34%), T93M (602858.0009) (8/64, 12.5%), and V326L (602858.0011) (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. The authors estimated that 33 to 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol, suggesting that factors other than plasma cholesterol are additionally involved in determining severity.

Krakowiak et al. (2000) reported clinical and molecular data concerning 16 patients with SLOS of varying phenotypic severity. In each they identified mutations in both alleles. They found 6 previously undescribed mutations. They also reported rapid PCR-based assays developed to detect 4 of the recurring mutations and 6 others.

Witsch-Baumgartner et al. (2001) reported mutation analysis of the DHCR7 gene in 59 SLOS patients, 28 of whom had previously been reported (Witsch-Baumgartner et al., 2000). Fifteen patients were from Poland, 22 from Germany/Austria, and 22 from Great Britain. Mutations were detected on 114 of 118 SLOS chromosomes (96.6%). Altogether, 35 different mutations were identified, but in all 3 populations 3 mutations accounted for more than 50% of SLOS alleles. The mutation spectra were, however, significantly different across these populations. W151X (602858.0010) was the most frequent mutation in the Polish population (33.3%), had an intermediate frequency in German/Austrian patients (18.2%), and was rare in British patients (2.3%). The V326L mutation (602858.0011) showed the same east-west gradient. In contrast, IVS8-1G-C (602858.0001) was most frequent in Britain (34.1%), intermediate in Germany/Austria (20.5%), and rare in Poland (3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene gave evidence for both recurrent mutations and founder effects; all IVS8-1G-C and V326L alleles shared the same haplotype, whereas the W151X allele occurred on different haplotypes. Witsch-Baumgartner et al. (2001) concluded that the distribution pattern of DHCR7 mutations in Europe may reflect ancient and modern migrations in Europe.

Among 37 ethnic Polish patients with SLOS, Ciara et al. (2004) found that 2 mutations, W151X (602858.0010), present in 22 of 68 alleles (32%), and V326L (602858.0011), present in 19 of 68 alleles (28%), accounted for 60% of all mutations observed in this group.

Scalco et al. (2005) reported on DHCR7 mutation analysis of 14 Brazilian SLOS patients. The most frequent mutations in this population were the IVS8-1G-C (602858.0001) and T93M (602858.0009) mutations. A mutation disrupting the normal initiation codon (M1V; 602858.0020) was identified in a mildly affected child. Langius et al. (2003) had reported a mutation in the initiator methionine (M1L; 602858.0017) in 3 patients who were also mildly affected. Wassif et al. (1998) had previously shown that initiation of translation at met59 gives rise to a functional protein. Both Langius et al. (2003) and Scalco et al. (2005) suspected that protein initiation at met59 allows for synthesis of a functional DHCR7 enzyme, accounting for the mild nature of the disorder in these mutations of the initiator methionine.

Nowaczyk et al. (2006) pointed out that the carrier rate for the most frequently occurring DHCR7 mutation causing SLOS, IVS8-1G-C (602858.0001), is approximately 1 in 100 for the Caucasian population of North America and possibly as high as 1 in 50 to 1 in 30 in central European populations. Based on the frequencies and the proportion of this mutation observed in various patient populations, the expected incidence of SLOS in those populations was calculated to be between 1 and 1,590 and 1 in 17,000. However, around the world the observed prevalence and incidence are much lower than those calculated from the individual mutation carrier rates observed in any given population. The discrepancy between the expected incidence and prevalence can be explained only in part by the neonatal and infancy deaths of the most severely affected children with SLOS and underascertainment of mild and atypical cases at the mild end of the spectrum. SLOS may be responsible for a high number of miscarriages. Estimates of the prevalence of SLOS at 16 weeks' gestation are similar to that observed at birth (approximately 1 in 60,000), suggesting that either reduced fertility of carrier couples or losses of affected embryos or fetuses in the first trimester play a significant role in reducing the second trimester prevalence of SLOS. One hypothesis postulated that null mutations of DHCR7 confer an advantage in increasing endogenous vitamin D synthesis (Kelley and Hennekam, 2000). Since osteomalacia was a common disease in Europe since antiquity, it is possible that individuals that were protected from this disease, especially in the northern parts of Europe, were at a survival advantage. Opitz et al. (2002) suggested that higher levels of 7-dehydrocholesterol in carrier females may have reduced the frequency of cephalopelvic disproportion in fetuses at risk for rickets secondary to maternal vitamin D deficiency and thus, provide a fertility advantage. Kelley and Herman (2001) discussed the biases that may be at play in estimating the carrier rates of DHCR7 mutations based on the mutation spectrum observed in the affected population and assuming that it is representative of the frequencies of various mutations in carriers.


Animal Model

Wassif et al. (2001) developed a mouse model of RSH/SLOS by disruption of the 3-beta-hydroxysterol delta-7-reductase gene. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intrauterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia, and decreased movement. Neurophysiologic studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired.

Cholesterol-enriched lipid rafts play an important role in mast cell activation. Kovarova et al. (2006) observed that mast cells derived from Dhcr7 -/- mice showed constitutive cytokine production and hyperdegranulation after stimulation of Fcer1 (see FCER1A, 147140). Dhcr7-deficient mast cells accumulated 7-DHC in lipid rafts, partially disrupting raft stability and displacing Lyn (165120) protein and activity. Downregulation of Lyn-dependent signaling events, such as phosphorylation of Csk-binding protein (PAG; 605767), was associated with increased Fyn (137025) kinase activity and Akt (164730) phosphorylation. Kovarova et al. (2006) proposed that lipid raft dysfunction in SLOS may explain the observation of allergy in these patients due to increased mast cell sensitivity.


ALLELIC VARIANTS ( 22 Selected Examples):

.0001 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, IVS8AS, G-C, -1
  
RCV000007178

A G-to-C transversion in intron 8 of the DHCR7 gene results in a splice site defect and a null mutation, and is the most common mutant allele in Smith-Lemli-Opitz syndrome (SLOS; 270400) (Wright et al., 2003).

In cell line A2SLO from a patient with severe SLOS, Wassif et al. (1998) identified a 134-bp insertion between nucleotides 788 and 789 of the DHCR7 gene. The insertion resulted in a frameshift, starting at amino acid 263, that precluded translation of the highly conserved carboxyl end of the protein. The cell line was homozygous for the insertion.

In a patient with severe SLOS, the first child of unrelated parents, Waterham et al. (1998) found homozygosity for a 134-bp insertion in the DHCR7 gene after nucleotide 963. Yu et al. (2000) noted that the IVS8-1G-C mutation results in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop. The more severe phenotype in this patient was consistent with the fact that the insertion occurred in a region strongly conserved among sterol reductases. Both parents were heterozygous for the insertion. Waterham et al. (1998) found the 134-bp insertion in compound heterozygous state in a child with SLOS, the other allele carrying the trp248-to-cys mutation (602858.0008) in the DHCR7 gene.

Among 16 patients with severe SLOS (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 14 of 32 mutant alleles carried an IVS8-1G-C mutation in the DHCR7 gene.

Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for the rapid detection of this mutation, which they identified in 21 of 66 alleles. The authors concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S.

Witsch-Baumgartner et al. (2001) detected the IVS8-1G-C mutation on 25 of 118 alleles (21.2%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected (Great Britain, 34.1% of alleles; Germany/Austria, 20.5%; Poland, 3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 13 IVS8-1G-C chromosomes shared the same haplotype and therefore provided evidence for a founder effect. One IVS8-1G-C mutation was present in cis with a T93M mutation (602858.0009) on a different haplotype. As one of the other T93M alleles was also characterized by this haplotype, the double mutant was consistent with a recombination event.

Krakowiak et al. (2000) detected this mutation in compound heterozygosity with thr289 to ile (602858.0015) in 2 brothers with SLOS. Nowaczyk et al. (2001) found that the boys' female first cousin carried the IVS8-1G-C/T289I genotype as well. The 2 unrelated mothers were carriers of the IVS8-1G-C mutation.

Nowaczyk et al. (2001) found the IVS8-1G-C mutation in homozygous state in a fetus and 2 newborns with severe SLOS and holoprosencephaly. They stated that of the 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had HPE.

The IVS8-1G-C mutation is the most frequently identified mutant allele, accounting for approximately one-third of reported SLOS alleles. Wright et al. (2003) screened for this mutation in African Americans and found a carrier frequency of 0.73% (10 of 1378), which predicted a homozygosity incidence of 1 of 75,061. They suggested that it is likely that the IVS8-1G-C allele appeared in the African American population through admixture. Witsch-Baumgartner et al. (2001) suggested that this mutation is a founder mutation that arose in the British Isles.

Scalco et al. (2005) detected the IVS8-1G-C mutation on 10 of 28 alleles (36%) in a study of 14 SLOS patients from Brazil. In 7 patients, the IVS8-1G-C mutation was found in compound heterozygosity with the T93M mutation (602848.0009).

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the IVS8-1G-C mutation, which they called 964-1G-C, appeared about 3,000 years ago in northwest Europe.


.0002 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 96-BP DEL
   RCV000007179

Wassif et al. (1998) found that a cell line (B3SLO) from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) was compound heterozygous for a 96-bp deletion and for insertion of a single cytosine between nucleotides 505 and 506 (602858.0003). The deletion extended from nucleotide -77 to nucleotide 19. It potentially removed the start codon. Neither of the 2 ATGs present in the undeleted 5-prime region were in-frame, and the next in-frame ATG encoded amino acid 138. The 1-bp insertion resulted in both a frameshift starting at amino acid 170 and addition of 39 aberrant amino acids.


.0003 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 1-BP INS, 505C
   RCV000007180

For discussion of the 1-bp insertion in the DHCR7 gene (505_506insC) that was found in compound heterozygous state in a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) by Wassif et al. (1998), see 602858.0002.


.0004 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 1-BP INS, 586T
   RCV000007181

In cell line C4SLO from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400), Wassif et al. (1998) identified insertion of a single thymidine between nucleotides 586 and 587 (586_587insT). The result of this insertion was both a frameshift starting at amino acid 197 and the addition of 12 aberrant amino acids. The mutation precluded normal translation of the highly conserved C-terminal half of the protein. The second mutation in the C4SLO cell line was not identified.


.0005 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, HIS119LEU
  
RCV000007182...

In a boy born to unrelated parents with features of Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for his119-to-leu and gly244-to-arg (602858.0006) mutations in the delta-7-dehydrocholesterol reductase gene. The boy was hypotonic at birth and showed microcephaly, micrognathia, craniofacial abnormalities, postaxial polydactyly of both hands, bilateral syndactyly of the second and third toes, and ambiguous genitalia that appeared to be severe hypospadias with micropenis. At 1 year of age he showed severe developmental delay. The first of the amino acid substitutions in this patient was due to a 356A-T transversion inherited from the mother; the second was due to a 730G-A transition inherited from the father.


.0006 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, GLY244ARG
  
RCV000007183...

For discussion of the gly244-to-arg (G244R) mutation in the DHCR7 gene that was found in compound heterozygous state in a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400) by Waterham et al. (1998), see 602858.0005.


.0007 MOVED TO 602858.0001


.0008 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP248CYS
  
RCV000007184

In an infant with Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for a 134-bp insertion (602858.0001) and a 744G-T transversion that resulted in a trp248-to-cys substitution in the DHCR7 gene. (Yu et al. (2000) noted that the IVS8-1G-C mutation (602858.0001) resulted in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop.) The boy was born at term after a pregnancy complicated by intrauterine growth retardation. At birth, the boy was microcephalic and showed multiple dysmorphic features, including a broad nasal tip with anteverted nostrils, a cleft soft palate, broad alveolar ridges, micrognathia, syndactyly of the second and third toes, and a small penis with cryptorchidism. At 3 years of age, the boy had psychomotor retardation, severe failure to thrive, and feeding difficulties that still necessitated tube feeding. SLO syndrome was biochemically diagnosed on the basis of low plasma cholesterol and high 7-dehydrocholesterol concentrations, and was confirmed by the finding of greatly reduced 7-DHCR activity in cultured skin fibroblasts, as determined by 14-C-mevalonate incorporation.


.0009 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, THR93MET
  
RCV000007185...

In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) identified a heterozygous C-to-T transition at nucleotide 278 of the DHCR7 gene, resulting in a thr93-to-met substitution (T93M). De Brasi et al. (1999) found that T93M was the most frequent mutation in 9 Italian patients with SLOS, occurring in 7 of 18 alleles.

Witsch-Baumgartner et al. (2001) detected the T93M mutation on 3 of 44 alleles (6.8%) in a study of 22 SLOS patients from Great Britain. The mutation was not detected in 22 SLOS patients from Germany/Austria or 15 patients from Poland.

Scalco et al. (2005) detected the T93M mutation on 9 of 28 alleles (32%) in a study of 14 SLOS patients from Brazil. In 7 patients, the T93M mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001).

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the T93M mutation probably arose about 6,000 years ago in the eastern Mediterranean region.

Kalb et al. (2012) identified the T93M mutation in 9 (36%) of 26 mutant alleles from 13 Turkish patients with SLO syndrome. Three probands were homozygous for the mutation. No carriers of T93M were identified in 771 control individuals. The allele frequency was estimated to be no more than 1 in 420.


.0010 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP151TER
  
RCV000007186

In 16 patients with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 5 of the 32 disease alleles carried a G-to-A transition at nucleotide 453 of the DHCR7 gene, resulting in a trp151-to-ter substitution (W151X).

Loffler et al. (2000) reported 2 sibs with severe, lethal SLOS due to homozygosity for the null mutation W151X. One sib died at age 19 days, whereas the other was a pregnancy termination at 20 weeks' gestation.

Witsch-Baumgartner et al. (2001) detected the W151X mutation on 19 of 118 alleles (16.1%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 33.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that the W151X mutation occurred on 3 different haplotypes. As these haplotypes differed only at single nucleotide positions and therefore may be derived from the same ancestral haplotype, the authors could not distinguish between the possibility that this mutation is a recurrent mutation or is very old and has spread to different haplotypes.

Ciara et al. (2004) found the W151X mutation in 22 of 68 alleles (32%) in a study of 37 ethnic Polish patients.

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the W151X mutation appeared about 3,000 years ago in northeast Europe.


.0011 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, VAL326LEU
  
RCV000007187...

In 5 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in a val326-to-leu (V326L) amino acid substitution. In 3 of these patients the V326L mutation was found in compound heterozygous state, whereas in the other 2 patients the V326L mutation was found on 1 allele only. SSCP analysis failed to reveal a second mutation in these 2 patients.

In a screen of 32 patients with SLOS, Yu et al. (2000) found that the V326L mutation accounted for 5 of 64 alleles (7.8%), making it the third most common mutation observed in their cohort. The first and second most prevalent mutations were IVS8-1G-C (602858.0001) and T93M (602858.0009), respectively.

Witsch-Baumgartner et al. (2001) detected the V326L mutation on 16 of 118 alleles (13.6%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 23.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 5 V326L chromosomes shared the same haplotype and therefore provided evidence for a founder effect.

Ciara et al. (2004) found the V326L mutation in 19 of 68 alleles (28%) in a study of 37 ethnic Polish patients.


.0012 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP37TER
  
RCV000169596

Among 32 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) found 1 patient with a G-to-A transition in exon 4 in one allele of the DHCR7 gene, resulting in a trp37-to-ter substitution (W37X).


.0013 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG352TRP
  
RCV000007189...

Witsch-Baumgartner et al. (2001) detected an R352W mutation on 7 (5.9%) of 118 alleles in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected for this mutation (Poland, 13.3% of alleles; Germany/Austria, 6.8%; Great Britain, none).


.0014 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG404CYS
  
RCV000007190...

Witsch-Baumgartner et al. (2001) detected an R404C mutation on 5 (4.2%) of 118 alleles of the DHCR7 gene in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected for this mutation (Great Britain, 9.1% of alleles; Germany/Austria, 2.3%; Poland, none).


.0015 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, THR289ILE
  
RCV000007191...

In 2 brothers with Smith-Lemli-Opitz syndrome (SLOS; 270400) described by Nowaczyk et al. (1998), Krakowiak et al. (2000) detected a C-to-T transition at nucleotide position 866 of the DHCR7 gene, resulting in a change from threonine to isoleucine at codon 289 (T289I). The T289I mutation occurs between the sixth and seventh transmembrane domain of the DHCR7 protein. This mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001). Nowaczyk et al. (2001) extended study of these patients to their parents and female first cousin. The brothers' father carried the T289I missense mutation. The cousin, like the brothers, carried the IVS8-1G-C/T289I genotype.


.0016 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TYR280CYS
  
RCV000007192...

In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Prasad et al. (2002) found compound heterozygosity for the common IVS8-1G-C (602858.0001) mutation and a tyr280-to-cys (Y280C) mutation in DHCR7. The exceptionally mildly affected female infant presented initially with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of the toes in both feet. Plasma cholesterol was borderline low at 2.88 mmol/L. Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Since the common mutation in this patient was a known null mutation, the Y280C mutation was presumably associated with significant residual enzyme activity leading to milder expression of the clinical phenotype.


.0017 SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, MET1LEU
  
RCV000169218...

Langius et al. (2003) found compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation affecting translation initiation of met1 to leu (M1L) in the DHCR7 gene in 2 brothers with a very mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400). The 15-year-old brother was described as having a relatively high forehead and broad nasal bridge as well as a relatively small chin. He showed second and third toe syndactyly and hypospadias. The 10-year-old younger brother likewise had syndactyly of the second and third toes as well as clinodactyly of the left second finger.


.0018 SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, GLU448LYS
  
RCV000020435...

Langius et al. (2003) described a 12-year-old girl with a very mild form of Smith-Lemli-Opitz (SLOS; 270400) found to be caused by compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation, M1L (602858.0017), in the DHCR7 gene. In addition, she was found to have a 1342G-A mutation, resulting in a glu448-to-lys (E448K) substitution. Head circumference was at the -3 standard deviations at birth and at the age of 12 she had bilateral second and third toe syndactyly and a high forehead.


.0019 SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, PHE284LEU
  
RCV000815482...

In a patient with very mild Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) identified compound heterozygosity for 2 mutations in the DHCR7 gene: phe284 to leu (F284L), just outside the transmembrane domain on exon 8, and the more common val326 to leu (V326L; 602858.0011), in the transmembrane domain on exon 9. Mueller et al. (2003) described the clinical features of this patient. Developmentally, the child demonstrated mild delays in gross motor skills associated with mild hypotonia. Cognitive, language, and motor abilities were all within the low average range for her age, between the 14th and 18th centiles. She had not demonstrated temper tantrums, motor stereotypes, sleep disturbance, or hypersensitivity to light and sound as shown by many SLOS patients. The patient had presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. Physical examination showed subtle 2,3 syndactyly. Her 7-dehydrocholesterol level was markedly elevated, and her cholesterol level was normal. Cholesterol supplementation implemented at 3 months of age resulted in increased cholesterol levels and reduced dehydrocholesterol levels. MRI of the brain showed no abnormalities.


.0020 SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, MET1VAL
  
RCV000169384...

In a patient with a mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400), Scalco et al. (2005) found a 1A-G transition, resulting in a met1-to-val (M1V) substitution of the initiator codon of the DHCR7 gene. The authors proposed that protein initiation at met59, which was demonstrated by Wassif et al. (1998) to result in a functional DHCR7 protein, could account for the mild phenotype.


.0021 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG352GLN
  
RCV000007197...

In 7 unrelated Japanese patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Matsumoto et al. (2005) identified a 1055G-A transition in exon 9 of the DHCR7 gene, resulting in an arg352-to-gln (R352Q) substitution within the eighth transmembrane domain, which is a highly conserved sterol-sensing region. Two patients were homozygous for the R352Q mutation, and it occurred in 9 of 14 mutant alleles. Haplotype analysis indicated a founder effect.


.0022 SMITH-LEMLI-OPITZ SYNDROME

DHCR7, IVS5DS, A-T, +3
  
RCV000023212

In a girl with Smith-Lemli-Opitz syndrome (SLOS; 270400), Koo et al. (2010) identified compound heterozygosity for 2 mutations in the DHCR7 gene: the common IVS8-1G-C splice site mutation (602858.0001) and an A-to-T transversion in intron 5 (IVS5+3A-T), resulting in the skipping of exon 5, a frameshift, and premature termination. RT-PCR studies of patient fibroblasts showed 3 bands, including a wildtype band, indicating that some residual wildtype protein was produced from the IVS5+3A-T mutation. However, patient fibroblasts showed a defect in sterol synthesis in cholesterol-deficient medium. The patient had a severe form of the disorder at birth, with multiple congenital anomalies affecting many organ systems, but after birth she showed less neurologic impairment than expected. She rolled from side to side at age 7 months, could stand with assistance at 11 months, and gained some fine motor control. Serum 7-dehydrocholesterol was increased at age 4 months but later fell to normal range, and serum cholesterol was normal. Compared to patients with a more severe phenotype and with a less severe phenotype, Koo et al. (2010) observed a discordance in this patient: she was more severely affected, but had a lower 7-dehydrocholesterol/cholesterol ratio, which was usually observed in less severely affected individuals. Koo et al. (2010) noted that there is a high need for cholesterol during embryonic development, which may have explained why this child was born with so many abnormalities. After birth, the residual enzyme activity conferred by the IVS5+3A-T mutation and the addition of dietary cholesterol may have been sufficient to allow some developmental acquisition.


REFERENCES

  1. Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M. DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. Clin. Genet. 66: 517-524, 2004. [PubMed: 15521979, related citations] [Full Text]

  2. De Brasi, D., Esposito, T., Rossi, M., Parenti, G., Sperandeo, M. P., Zuppaldi, A., Bardaro, T., Ambruzzi, M. A., Zelante, L., Ciccodicola, A., Sebastio, G., D'Urso, M., Andria, G. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta-7-sterol reductase in Italy and report of three novel mutations. Europ. J. Hum. Genet. 7: 937-940, 1999. [PubMed: 10602371, related citations] [Full Text]

  3. Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Nat. Acad. Sci. 95: 8181-8186, 1998. [PubMed: 9653161, images, related citations] [Full Text]

  4. Freitas, F. P., Alborzinia, H., Dos Santos, A. F., Nepachalovich, P., Pedrera, L., Zilka, O., Inague, A., Klein, C., Aroua, N., Kaushal, K., Kast, B., Lorenz, S. M., and 35 others. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature 626: 401-410, 2024. [PubMed: 38297129, related citations] [Full Text]

  5. Kalb, S., Caglayan, A. O., Degerliyurt, A., Schmid, S., Ceylaner, S., Hatipoglu, N., Hinderhofer, K., Rehder, H., Kurtoglu, S., Ceylaner, G., Zschocke, J., Witsch-Baumgartner, M. High frequency of p.thr93met in Smith-Lemli-Opitz syndrome patients in Turkey. (Letter) Clin. Genet. 81: 598-601, 2012. [PubMed: 22211794, related citations] [Full Text]

  6. Kelley, R. I., Hennekam, R. C. M. The Smith Lemli-Opitz syndrome. J. Med. Genet. 37: 321-335, 2000. [PubMed: 10807690, related citations] [Full Text]

  7. Kelley, R. I., Herman, G. E. Inborn errors of sterol biosynthesis. Annu. Rev. Genomics Hum. Genet. 2: 299-341, 2001. [PubMed: 11701653, related citations] [Full Text]

  8. Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 152A: 2094-2098, 2010. [PubMed: 20635399, related citations] [Full Text]

  9. Kovarova, M., Wassif, C. A., Odom, S., Liao, K., Porter, F. D., Rivera, J. Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness. J Exp Med. 203: 1161-1171, 2006. [PubMed: 16618793, images, related citations] [Full Text]

  10. Krakowiak, P. A., Nwokoro, N. A., Wassif, C. A., Battaile, K. P., Nowaczyk, M. J. M., Connor, W. E., Maslen, C., Steiner, R. D., Porter, F. D. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am. J. Med. Genet. 94: 214-227, 2000. [PubMed: 10995508, related citations]

  11. Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 122A: 24-29, 2003. [PubMed: 12949967, related citations] [Full Text]

  12. Li, Y., Ran, Q., Duan, Q., Jin, J., Wang, Y., Yu, L., Wang, C., Zhu, Z., Chen, X., Weng, L., Li, Z., Wang, J., and 13 others. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 626: 411-418, 2024. [PubMed: 38297130, related citations] [Full Text]

  13. Loffler, J., Trojovsky, A., Casati, B., Kroisel, P. M., Utermann, G. Homozygosity for the W151X stop mutation in the delta-7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am. J. Med. Genet. 95: 174-177, 2000. [PubMed: 11078571, related citations] [Full Text]

  14. Matsumoto, Y., Morishima, K., Honda, A., Watabe, S., Yamamoto, M., Hara, M., Hasui, M., Saito, C., Takayanagi, T., Yamanaka, T., Saito, N., Kudo, H., Okamoto, N., Tsukahara, M., Matsuura, S. R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients. J. Hum. Genet. 50: 353-356, 2005. [PubMed: 16044199, related citations] [Full Text]

  15. Moebius, F. F., Fitzky, B. U., Lee, J. N., Paik, Y.-K., Glossmann, H. Molecular cloning and expression of the human delta-7-sterol reductase. Proc. Nat. Acad. Sci. 95: 1899-1902, 1998. [PubMed: 9465114, images, related citations] [Full Text]

  16. Mueller, C., Patel, S., Irons, M., Antshel, K., Salen, G., Tint, G. S., Bay, C. Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. Am. J. Med. Genet. 123A: 100-106, 2003. [PubMed: 14556255, images, related citations] [Full Text]

  17. Nowaczyk, M. J. M., Farrell, S. A., Sirkin, W. L., Velsher, L., Krakowiak, P. A., Waye, J. S., Porter, F. D. Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G-C genotype. Am. J. Med. Genet. 103: 75-80, 2001. [PubMed: 11562938, related citations] [Full Text]

  18. Nowaczyk, M. J. M., Heshka, T., Eng, B., Feigenbaum, A. J., Waye, J. S. DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 100: 162-163, 2001. [PubMed: 11298379, related citations] [Full Text]

  19. Nowaczyk, M. J. M., Waye, J. S., Douketis, J. D. DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: where are the patients? Am. J. Med. Genet. 140A: 2057-2062, 2006. [PubMed: 16906538, related citations] [Full Text]

  20. Nowaczyk, M. J. M., Whelan, D. T., Hill, R. E. Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings. Am. J. Med. Genet. 78: 419-423, 1998. [PubMed: 9714007, related citations] [Full Text]

  21. Opitz, J. M., Gilbert-Barness, E., Ackerman, J., Lowichik, A. Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions. Pediat. Path. Molec. Med. 21: 153-181, 2002. [PubMed: 11942534, related citations] [Full Text]

  22. Porter, J. A., Young, K. E., Beachy, P. A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255-258, 1996. Note: Erratum: Science 274: 1597 only, 1996. [PubMed: 8824192, related citations] [Full Text]

  23. Prasad, C., Marles, S., Prasad, A. N., Nikkel, S., Longstaffe, S., Peabody, D., Eng, B., Wright, S., Waye, J. S., Nowaczyk, M. J. M. Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype. Am. J. Med. Genet. 108: 64-68, 2002. [PubMed: 11857552, related citations] [Full Text]

  24. Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter) Am. J. Med. Genet. 136A: 278-281, 2005. [PubMed: 15952211, related citations] [Full Text]

  25. Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., Holick, M. F. Markedly inhibited 7-dehydrocholesterol-delta(7)-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J. Clin. Invest. 96: 1779-1785, 1995. [PubMed: 7560069, related citations] [Full Text]

  26. Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 63: 55-62, 1998. [PubMed: 9634533, related citations] [Full Text]

  27. Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., Grinberg, A., Steiner, R. D., Nwokoro, N. A., Kelley, R. I., Stewart, R. R., Porter, F. D. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. Hum. Molec. Genet. 10: 555-564, 2001. [PubMed: 11230174, related citations] [Full Text]

  28. Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am. J. Hum. Genet. 63: 329-338, 1998. [PubMed: 9683613, related citations] [Full Text]

  29. Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations. Europ. J. Hum. Genet. 9: 45-50, 2001. [PubMed: 11175299, related citations] [Full Text]

  30. Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 66: 402-412, 2000. [PubMed: 10677299, images, related citations] [Full Text]

  31. Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. J. Med. Genet. 45: 200-209, 2008. [PubMed: 17965227, related citations] [Full Text]

  32. Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M. Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter) Am. J. Med. Genet. 120A: 139-141, 2003. [PubMed: 12794707, related citations] [Full Text]

  33. Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000. [PubMed: 10814720, related citations] [Full Text]

  34. Yu, H., Tint, G. S., Salen, G., Patel, S. B. Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi. Am. J. Med. Genet. 90: 347-350, 2000. [PubMed: 10710236, related citations] [Full Text]


Bao Lige - updated : 03/04/2024
Cassandra L. Kniffin - updated : 6/28/2012
Cassandra L. Kniffin - updated : 1/10/2011
Cassandra L. Kniffin - updated : 8/15/2008
Victor A. McKusick - updated : 6/18/2007
Paul J. Converse - updated : 1/29/2007
Cassandra L. Kniffin - updated : 11/8/2005
Victor A. McKusick - updated : 9/21/2005
Victor A. McKusick - updated : 3/31/2005
Victor A. McKusick - updated : 1/14/2004
Victor A. McKusick - updated : 9/30/2003
Victor A. McKusick - updated : 6/23/2003
Victor A. McKusick - updated : 2/8/2002
Victor A. McKusick - updated : 9/25/2001
George E. Tiller - updated : 5/29/2001
Anne M. Stumpf - updated : 5/10/2001
Michael B. Petersen - updated : 4/27/2001
Sonja A. Rasmussen - updated : 12/13/2000
Victor A. McKusick - updated : 10/4/2000
George E. Tiller - updated : 8/8/2000
Sonja A. Rasmussen - updated : 4/24/2000
Victor A. McKusick - updated : 3/31/2000
Matthew B. Gross - updated : 3/8/2000
Victor A. McKusick - updated : 2/9/2000
Victor A. McKusick - updated : 9/15/1998
Creation Date:
Victor A. McKusick : 7/16/1998
mgross : 03/04/2024
carol : 03/22/2023
alopez : 03/21/2023
carol : 10/12/2015
carol : 3/23/2015
mcolton : 3/20/2015
carol : 9/26/2013
alopez : 11/12/2012
terry : 10/2/2012
carol : 7/2/2012
ckniffin : 6/28/2012
wwang : 1/31/2011
ckniffin : 1/10/2011
terry : 1/20/2010
wwang : 4/16/2009
wwang : 8/19/2008
ckniffin : 8/15/2008
alopez : 6/19/2007
terry : 6/18/2007
carol : 6/11/2007
ckniffin : 6/8/2007
alopez : 1/29/2007
terry : 11/16/2006
wwang : 11/17/2005
ckniffin : 11/8/2005
wwang : 10/21/2005
wwang : 10/12/2005
terry : 9/21/2005
wwang : 3/31/2005
terry : 3/31/2005
carol : 2/3/2005
carol : 11/18/2004
tkritzer : 1/15/2004
terry : 1/14/2004
cwells : 9/30/2003
cwells : 7/1/2003
terry : 6/23/2003
carol : 9/10/2002
alopez : 2/19/2002
terry : 2/8/2002
carol : 10/30/2001
carol : 9/28/2001
terry : 9/25/2001
cwells : 6/4/2001
cwells : 5/29/2001
cwells : 5/24/2001
alopez : 5/10/2001
mcapotos : 5/2/2001
mcapotos : 4/27/2001
joanna : 4/20/2001
joanna : 4/18/2001
mcapotos : 12/13/2000
mcapotos : 12/13/2000
carol : 10/4/2000
terry : 10/4/2000
alopez : 8/8/2000
alopez : 8/8/2000
alopez : 8/8/2000
carol : 5/4/2000
mcapotos : 5/1/2000
terry : 4/24/2000
terry : 4/24/2000
terry : 4/21/2000
mgross : 4/10/2000
terry : 3/31/2000
carol : 3/8/2000
mgross : 3/8/2000
terry : 2/9/2000
carol : 10/7/1998
carol : 9/15/1998
terry : 8/5/1998
alopez : 7/17/1998

* 602858

7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7


Alternative titles; symbols

STEROL DELTA-7-REDUCTASE


HGNC Approved Gene Symbol: DHCR7

SNOMEDCT: 43929004;   ICD10CM: E78.72;  


Cytogenetic location: 11q13.4     Genomic coordinates (GRCh38): 11:71,434,411-71,448,393 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q13.4 Smith-Lemli-Opitz syndrome 270400 Autosomal recessive 3

TEXT

Description

The DHCR7 gene encodes delta-7-sterol reductase (EC 1.3.1.21), the penultimate enzyme of mammalian sterol biosynthesis that converts 7-dehydrocholesterol (7-DHC) to cholesterol. This enzyme removes the C(7-8) double bond introduced by the sterol delta8-delta7 isomerases. In addition, its role in drug-induced malformations is known: inhibitors of the last step of cholesterol biosynthesis such as AY9944 and BM15766 severely impair brain development (Moebius et al., 1998).


Cloning and Expression

Wassif et al. (1998) cloned a cDNA encoding human sterol delta-7-reductase (DHCR7) on the basis of its homology with the sterol delta-7-reductase from Arabidopsis thaliana, and they confirmed the enzymatic function of the human gene product by expression in fibroblasts.

Waterham et al. (1998) identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the EST database with the amino acid sequence of an A. thaliana enzyme. They isolated the remaining 5-prime sequence by 5-prime RACE. By heterologous expression of the cDNA in Saccharomyces cerevisiae, they confirmed that it coded for 7-dehydrocholesterol reductase.

Moebius et al. (1998) cloned the DHCR7 gene. The deduced protein is membrane-bound with a predicted molecular mass of 55 kD and 6 to 9 putative transmembrane segments. The protein is structurally related to plant and yeast sterol reductases. In adults, the ubiquitously transcribed mRNA is most abundant in adrenal gland, liver, testis, and brain. Although important in vertebrates, the enzyme is absent from yeast. Microsomes from Saccharomyces cerevisiae strains heterologously expressing the human cDNA removed the C(7-8) double bond in 7-dehydrocholesterol. The conversion to cholesterol depends on NADPH and is potently inhibited by AY9944, BM15766, and triparanol.


Mapping

Using radiation hybrid mapping, Wassif et al. (1998) mapped the DHCR7 gene to chromosome 11q12-q13. By FISH, Waterham et al. (1998) assigned the DHCR7 gene to 11q13.

Fitzky et al. (1998) characterized the human and mouse DHCR7 genes and assigned them to syntenic regions on 11q13 and 7F5, respectively, by FISH.


Gene Function

Porter et al. (1996) demonstrated that cholesterol is the lipophilic moiety covalently attached to the N-terminal signaling domain of hedgehog proteins (SHH, 600725; IHH, 600726) during autoprocessing and that the C-terminal domain acts as an intramolecular cholesterol transferase. They postulated that some of the effects of perturbed cholesterol biosynthesis on animal development may be due to the fact that cholesterol is used to modify embryonic signaling proteins. They postulated that in SLO syndrome, where cholesterol biosynthesis is defective, there may be defective modification of the hedgehog proteins and perhaps other similarly processed proteins. Porter et al. (1996) postulated further that the spectrum of developmental malformations seen in SLO syndrome may be due to loss of hedgehog protein function.

Using knockout screens in mouse Pfa1 cells, Freitas et al. (2024) identified Dhcr7 as a proferroptotic gene. DHCR7 knockout in the human ferroptosis fibrosarcoma cell line HT1080 led to accumulation of 7-DHC and resistance to ferroptosis, whereas reexpression of DHCR7 abolished 7-DHC concentrations and resensitized cells to ferroptosis. The accumulated 7-DHC in response to DHCR7 knockout functioned as an antiferroptotic metabolite that blocked peroxidation of phospholipids, resulting in truncated phospholipids that prevented execution of ferroptosis to protect cells. In addition, 7-DHC accumulation increased cell fitness and appeared to have in impact on lymphoma growth in a mouse model.

By knockdown screens in HEK293T cells, Li et al. (2024) independently identified DHCR7 as a proferroptotic gene. DHCR7 knockout strongly suppressed ferroptosis, whereas reexpression of DHCR7 reversed ferroptosis resistance in DHCR7-knockout cells. Loss of DHCR7 resulted in accumulation of 7-DHC, which protected the cells from ferroptosis by inhibiting peroxidation of phospholipids. 7-DHC was also involved in regulation of tumor ferroptosis and protection of kidneys from ischemia-reperfusion injury in a mouse model.


Molecular Genetics

Children with the Smith-Lemli-Opitz syndrome (SLOS; 270400) have elevated serum 7-DHC levels and low serum cholesterol levels. In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol delta-7-reductase. Liver microsomes from an SLOS homozygote were shown by Shefer et al. (1995) to have reduced activity of this enzyme.

In 3 unrelated patients with SLOS, Wassif et al. (1998) identified 4 different mutations in the DHCR7 gene (602858.0001-602858.0004). Fitzky et al. (1998) identified mutations in the DHCR7 gene (see, e.g., 602858.0009 and 602858.0011) in patients with SLOS. Waterham et al. (1998) identified homozygous and compound heterozygous mutations in the DHCR7 gene, including the intron 8 splice-site mutation (602858.0001), in patients with SLOS.

De Brasi et al. (1999) stated that 19 mutations in the DHCR7 gene had been described; among these, mutations impairing the activity of the C terminus appeared to be the most severe. They performed mutation analysis of the DHCR7 gene in 9 Italian SLOS patients and identified 3 novel mutations. They found that the T93M mutation (602858.0009) was the most frequent (7 of 18 alleles) in their survey.

In 84 patients with clinically and biochemically characterized SLOS, Witsch-Baumgartner et al. (2000) identified 40 different mutations in the DHCR7 gene. All but 1 of their patients were white, the exception having mostly American Cherokee heritage. On the basis of mutation type and expression studies, the authors grouped the mutations into 4 classes: nonsense and splice site mutations resulting in putative null alleles, missense mutations in the transmembrane domains, mutations in the fourth cytoplasmic loop, and mutations in the C-terminal endoplasmic reticulum (ER) domain. All but 1 of the tested missense mutations reduced protein stability. The mildest clinical phenotypes were associated with transmembrane and C-terminal ER domain mutations, and the most severe types were associated with null alleles and mutations in the fourth cytoplasmic loop. Most homozygotes for null alleles had severe SLOS; 1 patient had a moderate phenotype. Homozygosity for null mutations in the DHCR7 gene appeared compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used. Given that only a few null mutations exist, the authors were surprised to find that 2 of them, IVS8-1G-C (602858.0001) and trp151 to ter (602858.0011), accounted for more than one-third of all mutant alleles. In a note added in proof, Witsch-Baumgartner et al. (2000) stated that 7 additional DHCR7 mutations had been detected in 12 patients with SLOS.

Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for rapid detection of the IVS8-1G-C mutation. This mutation results in abnormal splicing of exon 9 with a 134-bp insertion of intron 8 sequences, a resultant frameshift, and a premature translation stop (602858.0001). The authors identified this mutation in 21 of 33 SLOS propositi (21 of 66 alleles). Since none of their patients was homozygous for this mutation, the authors hypothesized that homozygosity for the mutation may often be prenatally lethal. They also screened unrelated normal individuals for the prevalence of this mutation, including 90 American Caucasians, 120 Finnish Caucasians, 121 Sierra Leone Africans, 95 Han Chinese, and 103 Japanese. One IVS8-1G-C mutation was identified in the American Caucasian population; none was observed in the other populations. Yu et al. (2000) concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S.

Yu et al. (2000) screened an additional 32 patients with SLOS, 28 from the U.S.A. and 4 from Sweden. Twenty missense mutations, 1 nonsense mutation (602858.0012), and 1 splice-site mutation involving the exon 9 acceptor site (IVS8-1G-C; 602858.0001) were detected. All probands were heterozygous for mutations. Three mutations accounted for 54% of those observed in their cohort, the splice acceptor site mutation IVS8-1G-C (22/64 alleles, 34%), T93M (602858.0009) (8/64, 12.5%), and V326L (602858.0011) (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. The authors estimated that 33 to 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol, suggesting that factors other than plasma cholesterol are additionally involved in determining severity.

Krakowiak et al. (2000) reported clinical and molecular data concerning 16 patients with SLOS of varying phenotypic severity. In each they identified mutations in both alleles. They found 6 previously undescribed mutations. They also reported rapid PCR-based assays developed to detect 4 of the recurring mutations and 6 others.

Witsch-Baumgartner et al. (2001) reported mutation analysis of the DHCR7 gene in 59 SLOS patients, 28 of whom had previously been reported (Witsch-Baumgartner et al., 2000). Fifteen patients were from Poland, 22 from Germany/Austria, and 22 from Great Britain. Mutations were detected on 114 of 118 SLOS chromosomes (96.6%). Altogether, 35 different mutations were identified, but in all 3 populations 3 mutations accounted for more than 50% of SLOS alleles. The mutation spectra were, however, significantly different across these populations. W151X (602858.0010) was the most frequent mutation in the Polish population (33.3%), had an intermediate frequency in German/Austrian patients (18.2%), and was rare in British patients (2.3%). The V326L mutation (602858.0011) showed the same east-west gradient. In contrast, IVS8-1G-C (602858.0001) was most frequent in Britain (34.1%), intermediate in Germany/Austria (20.5%), and rare in Poland (3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene gave evidence for both recurrent mutations and founder effects; all IVS8-1G-C and V326L alleles shared the same haplotype, whereas the W151X allele occurred on different haplotypes. Witsch-Baumgartner et al. (2001) concluded that the distribution pattern of DHCR7 mutations in Europe may reflect ancient and modern migrations in Europe.

Among 37 ethnic Polish patients with SLOS, Ciara et al. (2004) found that 2 mutations, W151X (602858.0010), present in 22 of 68 alleles (32%), and V326L (602858.0011), present in 19 of 68 alleles (28%), accounted for 60% of all mutations observed in this group.

Scalco et al. (2005) reported on DHCR7 mutation analysis of 14 Brazilian SLOS patients. The most frequent mutations in this population were the IVS8-1G-C (602858.0001) and T93M (602858.0009) mutations. A mutation disrupting the normal initiation codon (M1V; 602858.0020) was identified in a mildly affected child. Langius et al. (2003) had reported a mutation in the initiator methionine (M1L; 602858.0017) in 3 patients who were also mildly affected. Wassif et al. (1998) had previously shown that initiation of translation at met59 gives rise to a functional protein. Both Langius et al. (2003) and Scalco et al. (2005) suspected that protein initiation at met59 allows for synthesis of a functional DHCR7 enzyme, accounting for the mild nature of the disorder in these mutations of the initiator methionine.

Nowaczyk et al. (2006) pointed out that the carrier rate for the most frequently occurring DHCR7 mutation causing SLOS, IVS8-1G-C (602858.0001), is approximately 1 in 100 for the Caucasian population of North America and possibly as high as 1 in 50 to 1 in 30 in central European populations. Based on the frequencies and the proportion of this mutation observed in various patient populations, the expected incidence of SLOS in those populations was calculated to be between 1 and 1,590 and 1 in 17,000. However, around the world the observed prevalence and incidence are much lower than those calculated from the individual mutation carrier rates observed in any given population. The discrepancy between the expected incidence and prevalence can be explained only in part by the neonatal and infancy deaths of the most severely affected children with SLOS and underascertainment of mild and atypical cases at the mild end of the spectrum. SLOS may be responsible for a high number of miscarriages. Estimates of the prevalence of SLOS at 16 weeks' gestation are similar to that observed at birth (approximately 1 in 60,000), suggesting that either reduced fertility of carrier couples or losses of affected embryos or fetuses in the first trimester play a significant role in reducing the second trimester prevalence of SLOS. One hypothesis postulated that null mutations of DHCR7 confer an advantage in increasing endogenous vitamin D synthesis (Kelley and Hennekam, 2000). Since osteomalacia was a common disease in Europe since antiquity, it is possible that individuals that were protected from this disease, especially in the northern parts of Europe, were at a survival advantage. Opitz et al. (2002) suggested that higher levels of 7-dehydrocholesterol in carrier females may have reduced the frequency of cephalopelvic disproportion in fetuses at risk for rickets secondary to maternal vitamin D deficiency and thus, provide a fertility advantage. Kelley and Herman (2001) discussed the biases that may be at play in estimating the carrier rates of DHCR7 mutations based on the mutation spectrum observed in the affected population and assuming that it is representative of the frequencies of various mutations in carriers.


Animal Model

Wassif et al. (2001) developed a mouse model of RSH/SLOS by disruption of the 3-beta-hydroxysterol delta-7-reductase gene. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intrauterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia, and decreased movement. Neurophysiologic studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired.

Cholesterol-enriched lipid rafts play an important role in mast cell activation. Kovarova et al. (2006) observed that mast cells derived from Dhcr7 -/- mice showed constitutive cytokine production and hyperdegranulation after stimulation of Fcer1 (see FCER1A, 147140). Dhcr7-deficient mast cells accumulated 7-DHC in lipid rafts, partially disrupting raft stability and displacing Lyn (165120) protein and activity. Downregulation of Lyn-dependent signaling events, such as phosphorylation of Csk-binding protein (PAG; 605767), was associated with increased Fyn (137025) kinase activity and Akt (164730) phosphorylation. Kovarova et al. (2006) proposed that lipid raft dysfunction in SLOS may explain the observation of allergy in these patients due to increased mast cell sensitivity.


ALLELIC VARIANTS 22 Selected Examples):

.0001   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, IVS8AS, G-C, -1
SNP: rs80338863, ClinVar: RCV000007178

A G-to-C transversion in intron 8 of the DHCR7 gene results in a splice site defect and a null mutation, and is the most common mutant allele in Smith-Lemli-Opitz syndrome (SLOS; 270400) (Wright et al., 2003).

In cell line A2SLO from a patient with severe SLOS, Wassif et al. (1998) identified a 134-bp insertion between nucleotides 788 and 789 of the DHCR7 gene. The insertion resulted in a frameshift, starting at amino acid 263, that precluded translation of the highly conserved carboxyl end of the protein. The cell line was homozygous for the insertion.

In a patient with severe SLOS, the first child of unrelated parents, Waterham et al. (1998) found homozygosity for a 134-bp insertion in the DHCR7 gene after nucleotide 963. Yu et al. (2000) noted that the IVS8-1G-C mutation results in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop. The more severe phenotype in this patient was consistent with the fact that the insertion occurred in a region strongly conserved among sterol reductases. Both parents were heterozygous for the insertion. Waterham et al. (1998) found the 134-bp insertion in compound heterozygous state in a child with SLOS, the other allele carrying the trp248-to-cys mutation (602858.0008) in the DHCR7 gene.

Among 16 patients with severe SLOS (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 14 of 32 mutant alleles carried an IVS8-1G-C mutation in the DHCR7 gene.

Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for the rapid detection of this mutation, which they identified in 21 of 66 alleles. The authors concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S.

Witsch-Baumgartner et al. (2001) detected the IVS8-1G-C mutation on 25 of 118 alleles (21.2%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected (Great Britain, 34.1% of alleles; Germany/Austria, 20.5%; Poland, 3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 13 IVS8-1G-C chromosomes shared the same haplotype and therefore provided evidence for a founder effect. One IVS8-1G-C mutation was present in cis with a T93M mutation (602858.0009) on a different haplotype. As one of the other T93M alleles was also characterized by this haplotype, the double mutant was consistent with a recombination event.

Krakowiak et al. (2000) detected this mutation in compound heterozygosity with thr289 to ile (602858.0015) in 2 brothers with SLOS. Nowaczyk et al. (2001) found that the boys' female first cousin carried the IVS8-1G-C/T289I genotype as well. The 2 unrelated mothers were carriers of the IVS8-1G-C mutation.

Nowaczyk et al. (2001) found the IVS8-1G-C mutation in homozygous state in a fetus and 2 newborns with severe SLOS and holoprosencephaly. They stated that of the 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had HPE.

The IVS8-1G-C mutation is the most frequently identified mutant allele, accounting for approximately one-third of reported SLOS alleles. Wright et al. (2003) screened for this mutation in African Americans and found a carrier frequency of 0.73% (10 of 1378), which predicted a homozygosity incidence of 1 of 75,061. They suggested that it is likely that the IVS8-1G-C allele appeared in the African American population through admixture. Witsch-Baumgartner et al. (2001) suggested that this mutation is a founder mutation that arose in the British Isles.

Scalco et al. (2005) detected the IVS8-1G-C mutation on 10 of 28 alleles (36%) in a study of 14 SLOS patients from Brazil. In 7 patients, the IVS8-1G-C mutation was found in compound heterozygosity with the T93M mutation (602848.0009).

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the IVS8-1G-C mutation, which they called 964-1G-C, appeared about 3,000 years ago in northwest Europe.


.0002   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 96-BP DEL
ClinVar: RCV000007179

Wassif et al. (1998) found that a cell line (B3SLO) from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) was compound heterozygous for a 96-bp deletion and for insertion of a single cytosine between nucleotides 505 and 506 (602858.0003). The deletion extended from nucleotide -77 to nucleotide 19. It potentially removed the start codon. Neither of the 2 ATGs present in the undeleted 5-prime region were in-frame, and the next in-frame ATG encoded amino acid 138. The 1-bp insertion resulted in both a frameshift starting at amino acid 170 and addition of 39 aberrant amino acids.


.0003   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 1-BP INS, 505C
ClinVar: RCV000007180

For discussion of the 1-bp insertion in the DHCR7 gene (505_506insC) that was found in compound heterozygous state in a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) by Wassif et al. (1998), see 602858.0002.


.0004   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, 1-BP INS, 586T
ClinVar: RCV000007181

In cell line C4SLO from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400), Wassif et al. (1998) identified insertion of a single thymidine between nucleotides 586 and 587 (586_587insT). The result of this insertion was both a frameshift starting at amino acid 197 and the addition of 12 aberrant amino acids. The mutation precluded normal translation of the highly conserved C-terminal half of the protein. The second mutation in the C4SLO cell line was not identified.


.0005   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, HIS119LEU
SNP: rs28938174, gnomAD: rs28938174, ClinVar: RCV000007182, RCV000274996

In a boy born to unrelated parents with features of Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for his119-to-leu and gly244-to-arg (602858.0006) mutations in the delta-7-dehydrocholesterol reductase gene. The boy was hypotonic at birth and showed microcephaly, micrognathia, craniofacial abnormalities, postaxial polydactyly of both hands, bilateral syndactyly of the second and third toes, and ambiguous genitalia that appeared to be severe hypospadias with micropenis. At 1 year of age he showed severe developmental delay. The first of the amino acid substitutions in this patient was due to a 356A-T transversion inherited from the mother; the second was due to a 730G-A transition inherited from the father.


.0006   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, GLY244ARG
SNP: rs121909764, gnomAD: rs121909764, ClinVar: RCV000007183, RCV001804715

For discussion of the gly244-to-arg (G244R) mutation in the DHCR7 gene that was found in compound heterozygous state in a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400) by Waterham et al. (1998), see 602858.0005.


.0007   MOVED TO 602858.0001


.0008   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP248CYS
SNP: rs104894212, ClinVar: RCV000007184

In an infant with Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for a 134-bp insertion (602858.0001) and a 744G-T transversion that resulted in a trp248-to-cys substitution in the DHCR7 gene. (Yu et al. (2000) noted that the IVS8-1G-C mutation (602858.0001) resulted in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop.) The boy was born at term after a pregnancy complicated by intrauterine growth retardation. At birth, the boy was microcephalic and showed multiple dysmorphic features, including a broad nasal tip with anteverted nostrils, a cleft soft palate, broad alveolar ridges, micrognathia, syndactyly of the second and third toes, and a small penis with cryptorchidism. At 3 years of age, the boy had psychomotor retardation, severe failure to thrive, and feeding difficulties that still necessitated tube feeding. SLO syndrome was biochemically diagnosed on the basis of low plasma cholesterol and high 7-dehydrocholesterol concentrations, and was confirmed by the finding of greatly reduced 7-DHCR activity in cultured skin fibroblasts, as determined by 14-C-mevalonate incorporation.


.0009   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, THR93MET
SNP: rs80338853, gnomAD: rs80338853, ClinVar: RCV000007185, RCV000079651, RCV000454251, RCV003985253

In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) identified a heterozygous C-to-T transition at nucleotide 278 of the DHCR7 gene, resulting in a thr93-to-met substitution (T93M). De Brasi et al. (1999) found that T93M was the most frequent mutation in 9 Italian patients with SLOS, occurring in 7 of 18 alleles.

Witsch-Baumgartner et al. (2001) detected the T93M mutation on 3 of 44 alleles (6.8%) in a study of 22 SLOS patients from Great Britain. The mutation was not detected in 22 SLOS patients from Germany/Austria or 15 patients from Poland.

Scalco et al. (2005) detected the T93M mutation on 9 of 28 alleles (32%) in a study of 14 SLOS patients from Brazil. In 7 patients, the T93M mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001).

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the T93M mutation probably arose about 6,000 years ago in the eastern Mediterranean region.

Kalb et al. (2012) identified the T93M mutation in 9 (36%) of 26 mutant alleles from 13 Turkish patients with SLO syndrome. Three probands were homozygous for the mutation. No carriers of T93M were identified in 771 control individuals. The allele frequency was estimated to be no more than 1 in 420.


.0010   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP151TER
SNP: rs104894213, rs11555217, gnomAD: rs11555217, ClinVar: RCV000007186

In 16 patients with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 5 of the 32 disease alleles carried a G-to-A transition at nucleotide 453 of the DHCR7 gene, resulting in a trp151-to-ter substitution (W151X).

Loffler et al. (2000) reported 2 sibs with severe, lethal SLOS due to homozygosity for the null mutation W151X. One sib died at age 19 days, whereas the other was a pregnancy termination at 20 weeks' gestation.

Witsch-Baumgartner et al. (2001) detected the W151X mutation on 19 of 118 alleles (16.1%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 33.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that the W151X mutation occurred on 3 different haplotypes. As these haplotypes differed only at single nucleotide positions and therefore may be derived from the same ancestral haplotype, the authors could not distinguish between the possibility that this mutation is a recurrent mutation or is very old and has spread to different haplotypes.

Ciara et al. (2004) found the W151X mutation in 22 of 68 alleles (32%) in a study of 37 ethnic Polish patients.

By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the W151X mutation appeared about 3,000 years ago in northeast Europe.


.0011   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, VAL326LEU
SNP: rs80338859, gnomAD: rs80338859, ClinVar: RCV000007187, RCV001550331

In 5 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in a val326-to-leu (V326L) amino acid substitution. In 3 of these patients the V326L mutation was found in compound heterozygous state, whereas in the other 2 patients the V326L mutation was found on 1 allele only. SSCP analysis failed to reveal a second mutation in these 2 patients.

In a screen of 32 patients with SLOS, Yu et al. (2000) found that the V326L mutation accounted for 5 of 64 alleles (7.8%), making it the third most common mutation observed in their cohort. The first and second most prevalent mutations were IVS8-1G-C (602858.0001) and T93M (602858.0009), respectively.

Witsch-Baumgartner et al. (2001) detected the V326L mutation on 16 of 118 alleles (13.6%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 23.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 5 V326L chromosomes shared the same haplotype and therefore provided evidence for a founder effect.

Ciara et al. (2004) found the V326L mutation in 19 of 68 alleles (28%) in a study of 37 ethnic Polish patients.


.0012   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TRP37TER
SNP: rs750345068, gnomAD: rs750345068, ClinVar: RCV000169596

Among 32 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) found 1 patient with a G-to-A transition in exon 4 in one allele of the DHCR7 gene, resulting in a trp37-to-ter substitution (W37X).


.0013   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG352TRP
SNP: rs80338860, gnomAD: rs80338860, ClinVar: RCV000007189, RCV000259783, RCV001252750, RCV003934805

Witsch-Baumgartner et al. (2001) detected an R352W mutation on 7 (5.9%) of 118 alleles in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected for this mutation (Poland, 13.3% of alleles; Germany/Austria, 6.8%; Great Britain, none).


.0014   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG404CYS
SNP: rs61757582, gnomAD: rs61757582, ClinVar: RCV000007190, RCV000723830, RCV001266513, RCV003407290

Witsch-Baumgartner et al. (2001) detected an R404C mutation on 5 (4.2%) of 118 alleles of the DHCR7 gene in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected for this mutation (Great Britain, 9.1% of alleles; Germany/Austria, 2.3%; Poland, none).


.0015   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, THR289ILE
SNP: rs121909765, gnomAD: rs121909765, ClinVar: RCV000007191, RCV000412788, RCV002371766

In 2 brothers with Smith-Lemli-Opitz syndrome (SLOS; 270400) described by Nowaczyk et al. (1998), Krakowiak et al. (2000) detected a C-to-T transition at nucleotide position 866 of the DHCR7 gene, resulting in a change from threonine to isoleucine at codon 289 (T289I). The T289I mutation occurs between the sixth and seventh transmembrane domain of the DHCR7 protein. This mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001). Nowaczyk et al. (2001) extended study of these patients to their parents and female first cousin. The brothers' father carried the T289I missense mutation. The cousin, like the brothers, carried the IVS8-1G-C/T289I genotype.


.0016   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, TYR280CYS
SNP: rs121909766, ClinVar: RCV000007192, RCV003407291

In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Prasad et al. (2002) found compound heterozygosity for the common IVS8-1G-C (602858.0001) mutation and a tyr280-to-cys (Y280C) mutation in DHCR7. The exceptionally mildly affected female infant presented initially with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of the toes in both feet. Plasma cholesterol was borderline low at 2.88 mmol/L. Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Since the common mutation in this patient was a known null mutation, the Y280C mutation was presumably associated with significant residual enzyme activity leading to milder expression of the clinical phenotype.


.0017   SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, MET1LEU
SNP: rs121909767, gnomAD: rs121909767, ClinVar: RCV000169218, RCV001528227

Langius et al. (2003) found compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation affecting translation initiation of met1 to leu (M1L) in the DHCR7 gene in 2 brothers with a very mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400). The 15-year-old brother was described as having a relatively high forehead and broad nasal bridge as well as a relatively small chin. He showed second and third toe syndactyly and hypospadias. The 10-year-old younger brother likewise had syndactyly of the second and third toes as well as clinodactyly of the left second finger.


.0018   SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, GLU448LYS
SNP: rs80338864, gnomAD: rs80338864, ClinVar: RCV000020435, RCV000790762

Langius et al. (2003) described a 12-year-old girl with a very mild form of Smith-Lemli-Opitz (SLOS; 270400) found to be caused by compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation, M1L (602858.0017), in the DHCR7 gene. In addition, she was found to have a 1342G-A mutation, resulting in a glu448-to-lys (E448K) substitution. Head circumference was at the -3 standard deviations at birth and at the age of 12 she had bilateral second and third toe syndactyly and a high forehead.


.0019   SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, PHE284LEU
SNP: rs184297154, gnomAD: rs184297154, ClinVar: RCV000815482, RCV002442731

In a patient with very mild Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) identified compound heterozygosity for 2 mutations in the DHCR7 gene: phe284 to leu (F284L), just outside the transmembrane domain on exon 8, and the more common val326 to leu (V326L; 602858.0011), in the transmembrane domain on exon 9. Mueller et al. (2003) described the clinical features of this patient. Developmentally, the child demonstrated mild delays in gross motor skills associated with mild hypotonia. Cognitive, language, and motor abilities were all within the low average range for her age, between the 14th and 18th centiles. She had not demonstrated temper tantrums, motor stereotypes, sleep disturbance, or hypersensitivity to light and sound as shown by many SLOS patients. The patient had presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. Physical examination showed subtle 2,3 syndactyly. Her 7-dehydrocholesterol level was markedly elevated, and her cholesterol level was normal. Cholesterol supplementation implemented at 3 months of age resulted in increased cholesterol levels and reduced dehydrocholesterol levels. MRI of the brain showed no abnormalities.


.0020   SMITH-LEMLI-OPITZ SYNDROME, MILD

DHCR7, MET1VAL
SNP: rs104886033, gnomAD: rs104886033, ClinVar: RCV000169384, RCV000224026, RCV001267308, RCV003390651

In a patient with a mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400), Scalco et al. (2005) found a 1A-G transition, resulting in a met1-to-val (M1V) substitution of the initiator codon of the DHCR7 gene. The authors proposed that protein initiation at met59, which was demonstrated by Wassif et al. (1998) to result in a functional DHCR7 protein, could account for the mild phenotype.


.0021   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, ARG352GLN
SNP: rs121909768, gnomAD: rs121909768, ClinVar: RCV000007197, RCV000254828

In 7 unrelated Japanese patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Matsumoto et al. (2005) identified a 1055G-A transition in exon 9 of the DHCR7 gene, resulting in an arg352-to-gln (R352Q) substitution within the eighth transmembrane domain, which is a highly conserved sterol-sensing region. Two patients were homozygous for the R352Q mutation, and it occurred in 9 of 14 mutant alleles. Haplotype analysis indicated a founder effect.


.0022   SMITH-LEMLI-OPITZ SYNDROME

DHCR7, IVS5DS, A-T, +3
SNP: rs786200926, ClinVar: RCV000023212

In a girl with Smith-Lemli-Opitz syndrome (SLOS; 270400), Koo et al. (2010) identified compound heterozygosity for 2 mutations in the DHCR7 gene: the common IVS8-1G-C splice site mutation (602858.0001) and an A-to-T transversion in intron 5 (IVS5+3A-T), resulting in the skipping of exon 5, a frameshift, and premature termination. RT-PCR studies of patient fibroblasts showed 3 bands, including a wildtype band, indicating that some residual wildtype protein was produced from the IVS5+3A-T mutation. However, patient fibroblasts showed a defect in sterol synthesis in cholesterol-deficient medium. The patient had a severe form of the disorder at birth, with multiple congenital anomalies affecting many organ systems, but after birth she showed less neurologic impairment than expected. She rolled from side to side at age 7 months, could stand with assistance at 11 months, and gained some fine motor control. Serum 7-dehydrocholesterol was increased at age 4 months but later fell to normal range, and serum cholesterol was normal. Compared to patients with a more severe phenotype and with a less severe phenotype, Koo et al. (2010) observed a discordance in this patient: she was more severely affected, but had a lower 7-dehydrocholesterol/cholesterol ratio, which was usually observed in less severely affected individuals. Koo et al. (2010) noted that there is a high need for cholesterol during embryonic development, which may have explained why this child was born with so many abnormalities. After birth, the residual enzyme activity conferred by the IVS5+3A-T mutation and the addition of dietary cholesterol may have been sufficient to allow some developmental acquisition.


REFERENCES

  1. Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M. DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. Clin. Genet. 66: 517-524, 2004. [PubMed: 15521979] [Full Text: https://doi.org/10.1111/j.1399-0004.2004.00350.x]

  2. De Brasi, D., Esposito, T., Rossi, M., Parenti, G., Sperandeo, M. P., Zuppaldi, A., Bardaro, T., Ambruzzi, M. A., Zelante, L., Ciccodicola, A., Sebastio, G., D'Urso, M., Andria, G. Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta-7-sterol reductase in Italy and report of three novel mutations. Europ. J. Hum. Genet. 7: 937-940, 1999. [PubMed: 10602371] [Full Text: https://doi.org/10.1038/sj.ejhg.5200390]

  3. Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc. Nat. Acad. Sci. 95: 8181-8186, 1998. [PubMed: 9653161] [Full Text: https://doi.org/10.1073/pnas.95.14.8181]

  4. Freitas, F. P., Alborzinia, H., Dos Santos, A. F., Nepachalovich, P., Pedrera, L., Zilka, O., Inague, A., Klein, C., Aroua, N., Kaushal, K., Kast, B., Lorenz, S. M., and 35 others. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature 626: 401-410, 2024. [PubMed: 38297129] [Full Text: https://doi.org/10.1038/s41586-023-06878-9]

  5. Kalb, S., Caglayan, A. O., Degerliyurt, A., Schmid, S., Ceylaner, S., Hatipoglu, N., Hinderhofer, K., Rehder, H., Kurtoglu, S., Ceylaner, G., Zschocke, J., Witsch-Baumgartner, M. High frequency of p.thr93met in Smith-Lemli-Opitz syndrome patients in Turkey. (Letter) Clin. Genet. 81: 598-601, 2012. [PubMed: 22211794] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01750.x]

  6. Kelley, R. I., Hennekam, R. C. M. The Smith Lemli-Opitz syndrome. J. Med. Genet. 37: 321-335, 2000. [PubMed: 10807690] [Full Text: https://doi.org/10.1136/jmg.37.5.321]

  7. Kelley, R. I., Herman, G. E. Inborn errors of sterol biosynthesis. Annu. Rev. Genomics Hum. Genet. 2: 299-341, 2001. [PubMed: 11701653] [Full Text: https://doi.org/10.1146/annurev.genom.2.1.299]

  8. Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 152A: 2094-2098, 2010. [PubMed: 20635399] [Full Text: https://doi.org/10.1002/ajmg.a.33540]

  9. Kovarova, M., Wassif, C. A., Odom, S., Liao, K., Porter, F. D., Rivera, J. Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness. J Exp Med. 203: 1161-1171, 2006. [PubMed: 16618793] [Full Text: https://doi.org/10.1084/jem.20051701]

  10. Krakowiak, P. A., Nwokoro, N. A., Wassif, C. A., Battaile, K. P., Nowaczyk, M. J. M., Connor, W. E., Maslen, C., Steiner, R. D., Porter, F. D. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am. J. Med. Genet. 94: 214-227, 2000. [PubMed: 10995508]

  11. Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 122A: 24-29, 2003. [PubMed: 12949967] [Full Text: https://doi.org/10.1002/ajmg.a.20207]

  12. Li, Y., Ran, Q., Duan, Q., Jin, J., Wang, Y., Yu, L., Wang, C., Zhu, Z., Chen, X., Weng, L., Li, Z., Wang, J., and 13 others. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 626: 411-418, 2024. [PubMed: 38297130] [Full Text: https://doi.org/10.1038/s41586-023-06983-9]

  13. Loffler, J., Trojovsky, A., Casati, B., Kroisel, P. M., Utermann, G. Homozygosity for the W151X stop mutation in the delta-7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis. Am. J. Med. Genet. 95: 174-177, 2000. [PubMed: 11078571] [Full Text: https://doi.org/10.1002/1096-8628(20001113)95:2<174::aid-ajmg16>3.0.co;2-9]

  14. Matsumoto, Y., Morishima, K., Honda, A., Watabe, S., Yamamoto, M., Hara, M., Hasui, M., Saito, C., Takayanagi, T., Yamanaka, T., Saito, N., Kudo, H., Okamoto, N., Tsukahara, M., Matsuura, S. R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients. J. Hum. Genet. 50: 353-356, 2005. [PubMed: 16044199] [Full Text: https://doi.org/10.1007/s10038-005-0267-3]

  15. Moebius, F. F., Fitzky, B. U., Lee, J. N., Paik, Y.-K., Glossmann, H. Molecular cloning and expression of the human delta-7-sterol reductase. Proc. Nat. Acad. Sci. 95: 1899-1902, 1998. [PubMed: 9465114] [Full Text: https://doi.org/10.1073/pnas.95.4.1899]

  16. Mueller, C., Patel, S., Irons, M., Antshel, K., Salen, G., Tint, G. S., Bay, C. Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease. Am. J. Med. Genet. 123A: 100-106, 2003. [PubMed: 14556255] [Full Text: https://doi.org/10.1002/ajmg.a.20491]

  17. Nowaczyk, M. J. M., Farrell, S. A., Sirkin, W. L., Velsher, L., Krakowiak, P. A., Waye, J. S., Porter, F. D. Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G-C genotype. Am. J. Med. Genet. 103: 75-80, 2001. [PubMed: 11562938] [Full Text: https://doi.org/10.1002/1096-8628(20010915)103:1<75::aid-ajmg1502>3.0.co;2-r]

  18. Nowaczyk, M. J. M., Heshka, T., Eng, B., Feigenbaum, A. J., Waye, J. S. DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. 100: 162-163, 2001. [PubMed: 11298379] [Full Text: https://doi.org/10.1002/ajmg.1227]

  19. Nowaczyk, M. J. M., Waye, J. S., Douketis, J. D. DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: where are the patients? Am. J. Med. Genet. 140A: 2057-2062, 2006. [PubMed: 16906538] [Full Text: https://doi.org/10.1002/ajmg.a.31413]

  20. Nowaczyk, M. J. M., Whelan, D. T., Hill, R. E. Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings. Am. J. Med. Genet. 78: 419-423, 1998. [PubMed: 9714007] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980806)78:5<419::aid-ajmg5>3.0.co;2-g]

  21. Opitz, J. M., Gilbert-Barness, E., Ackerman, J., Lowichik, A. Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions. Pediat. Path. Molec. Med. 21: 153-181, 2002. [PubMed: 11942534] [Full Text: https://doi.org/10.1080/15227950252852078]

  22. Porter, J. A., Young, K. E., Beachy, P. A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255-258, 1996. Note: Erratum: Science 274: 1597 only, 1996. [PubMed: 8824192] [Full Text: https://doi.org/10.1126/science.274.5285.255]

  23. Prasad, C., Marles, S., Prasad, A. N., Nikkel, S., Longstaffe, S., Peabody, D., Eng, B., Wright, S., Waye, J. S., Nowaczyk, M. J. M. Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype. Am. J. Med. Genet. 108: 64-68, 2002. [PubMed: 11857552] [Full Text: https://doi.org/10.1002/ajmg.10211]

  24. Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter) Am. J. Med. Genet. 136A: 278-281, 2005. [PubMed: 15952211] [Full Text: https://doi.org/10.1002/ajmg.a.30810]

  25. Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., Holick, M. F. Markedly inhibited 7-dehydrocholesterol-delta(7)-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J. Clin. Invest. 96: 1779-1785, 1995. [PubMed: 7560069] [Full Text: https://doi.org/10.1172/JCI118223]

  26. Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 63: 55-62, 1998. [PubMed: 9634533] [Full Text: https://doi.org/10.1086/301936]

  27. Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., Grinberg, A., Steiner, R. D., Nwokoro, N. A., Kelley, R. I., Stewart, R. R., Porter, F. D. Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. Hum. Molec. Genet. 10: 555-564, 2001. [PubMed: 11230174] [Full Text: https://doi.org/10.1093/hmg/10.6.555]

  28. Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am. J. Hum. Genet. 63: 329-338, 1998. [PubMed: 9683613] [Full Text: https://doi.org/10.1086/301982]

  29. Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations. Europ. J. Hum. Genet. 9: 45-50, 2001. [PubMed: 11175299] [Full Text: https://doi.org/10.1038/sj.ejhg.5200579]

  30. Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am. J. Hum. Genet. 66: 402-412, 2000. [PubMed: 10677299] [Full Text: https://doi.org/10.1086/302760]

  31. Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations. J. Med. Genet. 45: 200-209, 2008. [PubMed: 17965227] [Full Text: https://doi.org/10.1136/jmg.2007.053520]

  32. Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M. Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter) Am. J. Med. Genet. 120A: 139-141, 2003. [PubMed: 12794707] [Full Text: https://doi.org/10.1002/ajmg.a.10207]

  33. Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000. [PubMed: 10814720] [Full Text: https://doi.org/10.1093/hmg/9.9.1385]

  34. Yu, H., Tint, G. S., Salen, G., Patel, S. B. Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi. Am. J. Med. Genet. 90: 347-350, 2000. [PubMed: 10710236] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7]


Contributors:
Bao Lige - updated : 03/04/2024
Cassandra L. Kniffin - updated : 6/28/2012
Cassandra L. Kniffin - updated : 1/10/2011
Cassandra L. Kniffin - updated : 8/15/2008
Victor A. McKusick - updated : 6/18/2007
Paul J. Converse - updated : 1/29/2007
Cassandra L. Kniffin - updated : 11/8/2005
Victor A. McKusick - updated : 9/21/2005
Victor A. McKusick - updated : 3/31/2005
Victor A. McKusick - updated : 1/14/2004
Victor A. McKusick - updated : 9/30/2003
Victor A. McKusick - updated : 6/23/2003
Victor A. McKusick - updated : 2/8/2002
Victor A. McKusick - updated : 9/25/2001
George E. Tiller - updated : 5/29/2001
Anne M. Stumpf - updated : 5/10/2001
Michael B. Petersen - updated : 4/27/2001
Sonja A. Rasmussen - updated : 12/13/2000
Victor A. McKusick - updated : 10/4/2000
George E. Tiller - updated : 8/8/2000
Sonja A. Rasmussen - updated : 4/24/2000
Victor A. McKusick - updated : 3/31/2000
Matthew B. Gross - updated : 3/8/2000
Victor A. McKusick - updated : 2/9/2000
Victor A. McKusick - updated : 9/15/1998

Creation Date:
Victor A. McKusick : 7/16/1998

Edit History:
mgross : 03/04/2024
carol : 03/22/2023
alopez : 03/21/2023
carol : 10/12/2015
carol : 3/23/2015
mcolton : 3/20/2015
carol : 9/26/2013
alopez : 11/12/2012
terry : 10/2/2012
carol : 7/2/2012
ckniffin : 6/28/2012
wwang : 1/31/2011
ckniffin : 1/10/2011
terry : 1/20/2010
wwang : 4/16/2009
wwang : 8/19/2008
ckniffin : 8/15/2008
alopez : 6/19/2007
terry : 6/18/2007
carol : 6/11/2007
ckniffin : 6/8/2007
alopez : 1/29/2007
terry : 11/16/2006
wwang : 11/17/2005
ckniffin : 11/8/2005
wwang : 10/21/2005
wwang : 10/12/2005
terry : 9/21/2005
wwang : 3/31/2005
terry : 3/31/2005
carol : 2/3/2005
carol : 11/18/2004
tkritzer : 1/15/2004
terry : 1/14/2004
cwells : 9/30/2003
cwells : 7/1/2003
terry : 6/23/2003
carol : 9/10/2002
alopez : 2/19/2002
terry : 2/8/2002
carol : 10/30/2001
carol : 9/28/2001
terry : 9/25/2001
cwells : 6/4/2001
cwells : 5/29/2001
cwells : 5/24/2001
alopez : 5/10/2001
mcapotos : 5/2/2001
mcapotos : 4/27/2001
joanna : 4/20/2001
joanna : 4/18/2001
mcapotos : 12/13/2000
mcapotos : 12/13/2000
carol : 10/4/2000
terry : 10/4/2000
alopez : 8/8/2000
alopez : 8/8/2000
alopez : 8/8/2000
carol : 5/4/2000
mcapotos : 5/1/2000
terry : 4/24/2000
terry : 4/24/2000
terry : 4/21/2000
mgross : 4/10/2000
terry : 3/31/2000
carol : 3/8/2000
mgross : 3/8/2000
terry : 2/9/2000
carol : 10/7/1998
carol : 9/15/1998
terry : 8/5/1998
alopez : 7/17/1998