Alternative titles; symbols
HGNC Approved Gene Symbol: SLC26A2
SNOMEDCT: 14870002, 254055004, 58561002, 715672007; ICD10CM: Q77.5;
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:149,960,758-149,987,400 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Achondrogenesis Ib | 600972 | Autosomal recessive | 3 |
| Atelosteogenesis, type II | 256050 | Autosomal recessive | 3 | |
| De la Chapelle dysplasia | 256050 | Autosomal recessive | 3 | |
| Diastrophic dysplasia | 222600 | Autosomal recessive | 3 | |
| Diastrophic dysplasia, broad bone-platyspondylic variant | 222600 | Autosomal recessive | 3 | |
| Epiphyseal dysplasia, multiple, 4 | 226900 | Autosomal recessive | 3 |
Hastbacka et al. (1994) reported the positional cloning of the gene mutated in diastrophic dysplasia (DTD; 222600) by fine-structure linkage disequilibrium mapping. The gene was found to encode a novel sulfate transporter, and was thus symbolized DTDST. Impaired function of DTDST product would be expected to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause a clinical phenotype such as diastrophic dysplasia. A defect in sulfate transport was demonstrable in fibroblasts from a DTD patient. The full transcript was expected to be 8.4 kb.
Satoh et al. (1998) cloned a rat osteoblastic cell DTDST cDNA encoding a 739-amino acid protein that is 73% identical to the human coding sequence. Northern blot analysis suggested that expression is predominantly in cartilage and intestine. The rat gene contains at least 5 exons. Injection of rat and human DTDST cRNA into frog oocytes induces Na(+)-independent sulfate transport that can be inhibited by extracellular chloride and bicarbonate. Satoh et al. (1998) observed a similar activity profile in chondrocytes.
By positional cloning, Hastbacka et al. (1994) mapped the DTDST gene approximately 70 kb proximal to CSF1R on 5q32-q33.1.
Hastbacka et al. (1994) identified point mutations in non-Finnish patients with DTD. Three patients from 3 different countries, Germany, the Netherlands, and France, were found to be heterozygous for a single base deletion in codon 575 (AAG to AG; 606718.0001). An American patient was found to have a 3-prime splice acceptor site mutation from AG to AC in heterozygous state. A third mutation, found in a Canadian patient, involved a deletion of 1 nucleotide in codon 661 (ACA to AC). This deletion was predicted to lead to a premature translational stop after 5 codons with truncation of the last 10% of the protein, including half of the highly conserved region in the C-terminal cytoplasmic tail.
Superti-Furga et al. (1995, 1996) described mutations in the DTDST gene (see 606718.0001 and 606718.0005-606718.0008) in patients with achondrogenesis type IB (600972). Hastbacka et al. (1995, 1996) identified mutations in the DTDST gene (see 606718.0001-606718.0004) in atelosteogenesis type II (256050). Thus, both of these disorders are allelic to diastrophic dysplasia.
Hastbacka et al. (1999) reported identification of a Finnish DTD founder mutation, a GT-to-GC transition in the splice donor site of the previously undescribed 5-prime untranslated exon of the DTDST gene (606718.0010). The mutation acts by severely reducing mRNA levels. Among 84 DTD families in Finland, patients carried 2 copies of the mutation in 69 families, 1 copy in 14 families, and no copies in 1 family. Thus, roughly 90% of the Finnish DTD chromosomes carried the splice site mutation, which Hastbacka et al. (1999) designated DTDST(Fin). Unexpectedly, they found that 9 of the DTD chromosomes having the apparently ancestral haplotype did not carry the Finnish mutation but rather 2 other mutations. Eight of these chromosomes had an R279W mutation (606718.0002) and 1 had a V340 deletion (606718.0008). One possible explanation was that the 3 DTD mutations arose in a population in which this 'rare' haplotype was in fact common and conferred a heterozygote advantage in this population, resulting in an excess of DTD mutations on this haplotype which were then admixed with a larger population in which the haplotype was rare. There was, however, no evidence to support the existence of such an ancestral population or of a heterozygote advantage conferred by DTD chromosomes. A second possibility was that the chromosomes with the rare haplotype are more prone to mutation, although again there was no evidence to support such a hypothesis. Finally, a third possibility was, of course, that the presence of multiple mutations on a rare haplotype are simply a matter of chance.
Karniski (2001) compared the sulfate transport activity of 11 reported DTDST mutations upon expression in Xenopus oocytes. Five mutations, including G255E (606718.0003), delta-A1751 (606718.0001), R178X (606718.0005), and N425D (606718.0006) exhibited minimal sulfate transport function. Two mutations, delta-V340 (606718.0008) and R279W (606718.0002), transported sulfate at rates of 17% and 32%, respectively, of wildtype DTDST. Four mutations, including A715V (606718.0004), Q454P (606718.0009), and G678V (606718.0007), had rates of sulfate transport nearly equal to that of wildtype DTDST. In the Xenopus oocyte expression system, the correlation between residual transport function and the severity of human phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.
Rossi and Superti-Furga (2001) stated that over 30 mutations in the SLC26A2 gene had been observed, including 22 novel mutations that they reported.
Karniski (2004) expressed DTDST-mediated sulfate transport in human embryonic kidney (HEK) cells and determined that the wildtype protein was glycosylated and localized to the cell plasma membrane. Four mutations, R279W (606718.0002), A715V (606718.0004), Q454P (606718.0009), and C653S (606718.0011), stimulated sulfate transport at rates only 39 to 62% of wildtype DTDST and were properly localized, but were underexpressed compared to wildtype DTDST. The Q454P mutant was unique in that it was not properly glycosylated in HEK cells, and the G678V (606718.0007) mutant was trapped within the cytoplasm. There was no difference in sulfate transport activity between cells transfected with either the delta-V340 or the G678V mutations and control HEK cells. Individuals with severe achondrogenesis 1B phenotype had null mutations on both DTDST alleles. Heterozygotes for both a null mutation and a partial-function mutation exhibited either atelosteogenesis type 2 or DTD, whereas those homozygous for partial-function mutations exhibited the milder, recessive multiple epiphyseal dysplasia phenotype. In contrast to previous studies in Xenopus laevis oocytes (Karniski, 2001), there was a strong correlation between the severity of the phenotype and the level of residual transport function in mammalian cells.
In affected members of the original family with de la Chapelle dysplasia (DLCD; see 256050 and de la Chapelle et al., 1972), Bonafe et al. (2008) identified a homozygous mutation in the SLC26A2 gene (606718.0013). The findings confirmed that de la Chapelle dysplasia is allelic to other SLC26A2 disorders.
Using a targeted next-generation sequencing skeletal dysplasia panel, Barreda-Bonis et al. (2018) identified mutations in the SLC26A2 gene in a 14-year-old-girl and her maternal grandfather with EDM4. The girl was compound heterozygous for the common R279W mutation (606718.0002), inherited from her mother, and a S522F mutation (606718.0015), inherited from her father. Her grandfather was homozygous for the R279W mutation. The girl's mother was short (-3.53 SD), but was only a carrier of the R279W mutation.
Comparing the severity of ACG IB to that of DTD, Superti-Furga et al. (1996) noted that ACG IB patients appeared to have structural DTDST mutations on both chromosomes, whereas no DTD patient had been found to that time with 2 structural mutations in DTDST. Rather, there appeared to be a DTD-specific allele, present at a frequency approaching 1% in the Finnish population, having an intact coding region. This allele gives no detectable mRNA by Northern blot analysis, or at the most a very small amount. They noted that the 1751A deletion mutation (606718.0001) results in diastrophic dysplasia when compounded with the presumed reduced-expression allele frequent in Finland (606718.0010), but produces ACG IB when compounded with a second structural mutation on the other chromosome, such as N425D (606718.0006).
Superti-Furga et al. (1996) reviewed the 3 recessively inherited chondrodysplasias of decreasing severity caused by mutations in the DTDST gene: diastrophic dysplasia, atelosteogenesis type II, and achondrogenesis type IB. Homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type IB, whereas other structural or regulatory mutations usually result in one of the less severe phenotypes. The chondrodysplasias arising at the DTDST locus all have recessive inheritance.
In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W and R178X (606718.0005) mutations in the SLC26A2 gene. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.
In a girl with features suggesting diastrophic dysplasia but with other features usually observed in Desbuquois dysplasia (see 251450), such as neonatal scoliosis, flat acetabular roof, and proximal femur monkey wrench configuration (which was present in early but not later radiographs), Panzer et al. (2008) identified compound heterozygosity for mutations in the SLC26A2 gene: the common R178X mutation and a novel A133V mutation (606718.0014).
Forlino et al. (2005) generated Slc26a2-knockin mice with a partial loss of function of the sulfate transporter resulting from abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, recapitulating essential aspects of the human DTD phenotype. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth.
In 3 patients with diastrophic dysplasia (DTD; 222600) from Germany, the Netherlands, and France, respectively, Hastbacka et al. (1994) identified heterozygosity for a deletion of 1 nucleotide in codon 575 of the DTD gene (SLC26A2), converting AAG to AG; this mutation resulted in a frameshift, causing a premature translational stop after 9 codons that would eliminate the last 20% of the protein. The deletion destroyed a DdeI site and created a BfaI site, providing a simple assay for the presence of the mutation. The patients presumably carried a different DTD mutation on the other homolog. Examination of 100 normal chromosomes confirmed that the deletion was not a polymorphism.
Superti-Furga et al. (1996) found that this mutation, which they called the 1751A deletion, results in diastrophic dysplasia when compounded with the presumed reduced-expression allele frequent in Finland (606718.0010), but produces achondrogenesis type IB (ACG1B; 600972) when compounded with a second structural mutation on the other chromosome, such as N425D (606718.0006).
In a patient with atelosteogenesis type II (AO2; 256050), Hastbacka et al. (1996) identified compound heterozygosity for 1751delA and an 862C-T transition resulting in an R279W substitution (606718.0002) in the third extracellular loop.
Atelosteogeneis Type II and Diastrophic Dysplasia
For discussion of the arg279-to-trp (R279W) mutation in the SLC26A2 gene that was found in compound heterozygous state in a patient with atelosteogenesis type II (AO2; 256050) by Hastbacka et al. (1996), see 606718.0001.
Hastbacka et al. (1996) also found the R279W substitution in compound heterozygous state in 4 patients with diastrophic dysplasia (DTD; 222600).
Rossi et al. (1996) studied fibroblast cultures of 3 new patients with mutations in the DTDST gene: one with diastrophic dysplasia (the least severe of the conditions caused by DTDST mutations), one with the more severe atelosteogenesis type II, and one with an intermediate phenotype designated AO2/DTD. Reduced incorporation of inorganic sulfate into macromolecules was found in all 3. Each of the 3 patients was found to be heterozygous for R279W. In 2 patients (DTD and OA2/DTD), no other structural mutation was found, but PCR amplification and SSCP analysis of fibroblast cDNA showed reduced mRNA levels of the wildtype DTDST allele. Rossi et al. (1996) stated that these 2 patients may be compound heterozygotes for the 'Finnish' mutation which had as yet not been characterized at the DNA level and which was known to cause reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine-418 (606718.0012), predicting a frameshift with premature termination. This allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R297W mutation in a total of 11 patients with AO2 or DTD emphasized the overlap between these conditions. This mutation was not found in 8 analyzed patients with achondrogenesis type IB (ACG IB), the clinically most severe member of this family of chondrodysplasias, suggesting that the R279W mutation allows some residual activity of the sulfate transporter.
In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W and R178X (606718.0005) mutations in the SLC26A2 gene. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.
Multiple Epiphyseal Dysplasia 4
Superti-Furga et al. (1999) reported a 36-year-old man with a recessively inherited form of multiple epiphyseal dysplasia (EDM4; 226900) characterized by tall-normal stature, clubfoot, and an unusual double-layered patella. This man was found to have a homozygous R279W mutation in the DTDST gene product. Both healthy parents were heterozygous for this mutation. Analysis of the proband's fibroblasts showed a sulfate incorporation defect typical of disorders caused by DTDST mutations.
Huber et al. (2001) found the R279W mutation in homozygosity in affected members of 2 unrelated sibships with multiple epiphyseal dysplasia, who were initially thought to have isolated clubfoot.
Czarny-Ratajczak et al. (2001) identified the homozygous R279W mutation in 2 probands with multiple epiphyseal dysplasia and multipartite patella (see 226900).
Using a targeted next-generation sequencing skeletal dysplasia panel, Barreda-Bonis et al. (2018) identified mutations in the SLC26A2 gene in a 14-year-old girl and her maternal grandfather with EDM4. The girl was compound heterozygous for the R279W mutation, inherited from her mother, and a c.1565C-T transition, resulting in a ser522-to-phe (S522F; 606718.0015) substitution, inherited from her father. Her grandfather was homozygous for the R279W mutation. The girl's mother was short (-3.53 SD), but was only a carrier for the R279W mutation.
Patient 3 with atelosteogenesis type II (AO2; 256050) investigated by Hastbacka et al. (1996) was a compound heterozygote for a 791G-A transition in the SLC26A2 gene, leading to a G255E substitution that introduced a negative charge in the highly conserved fifth putative transmembrane domain of the protein, and a 2171C-T transition, leading to an A715V substitution (606718.0004) close to the C terminus of the protein.
For discussion of the ala715-to-val (A715V) mutation in the SLC26A2 gene that was found in compound heterozygous state in a patient with atelosteogenesis type II (AO2; 256050) by Hastbacka et al. (1996), see 606718.0003.
In 3 patients with achondrogenesis type IB (ACG1B; 600972), Superti-Furga et al. (1996) found compound heterozygosity for a 559C-T transition in the SLC26A2 gene, resulting in an R178X amino substitution. The nonsense mutation resulted in truncation of approximately 75% of the protein. In each of the 3 cases the other mutant allele was a structural mutation (see, e.g., 606718.0007).
In a Mexican girl with diastrophic dysplasia (DTD; 222600) presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II (AO2; 256050), Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W (606718.0002) and R178X mutations in the SLC26A2 gene; see 606718.0002. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.
In a girl with features suggesting diastrophic dysplasia but with other features usually observed in Desbuquois dysplasia (251450), such as neonatal scoliosis, flat acetabular roof, and proximal femur monkey wrench configuration (which was present in early but not later radiographs), Panzer et al. (2008) identified compound heterozygosity for mutations in the SLC26A2 gene: the common R178X mutation and a novel A133V mutation (606718.0014).
In a patient with achondrogenesis type IB (ACG1B; 600972), Superti-Furga et al. (1996) found compound heterozygosity for 2 structural mutations in the DTDST gene: a 1300A-G transition resulting in an asn425-to-asp (N425D) substitution in the ninth transmembrane domain, and a deletion of 1751A (606718.0001).
In a fetus with achondrogenesis type IB (ACG1B; 600972), Superti-Furga et al. (1996) identified a 2060G-T transversion in the SLC26A2 gene, resulting in a gly678-to-val (G678V) substitution in the cytoplasmic C terminus. The mutation was in compound heterozygosity with the R178X mutation (606718.0005).
Superti-Furga et al. (1996) found homozygosity for deletion of val340 of the SLC26A2 gene in 2 patients with achondrogenesis type IB (ACG1B; 600972). In 1 family, the parents were Turkish and consanguineous; in the other family, the parents were Hispanic and nonconsanguineous.
In a Japanese male fetus with ACG1B, Cai et al. (1998) identified homozygosity for deletion of val340. The mutation involves deletion of 1 of 3 GTT repeats at nucleotides 1039-1047. The GTT repeat may represent a deletion hotspot, thus explaining the occurrence of the deletion in different ethnic groups. The fetus was also homozygous for a thr689-to-ser (T689S) substitution. The T689S mutation appeared to be a polymorphism, as it was detected in 5 alleles of 26 healthy Japanese individuals. The T689S mutation was thought not to be pathologic because it was located in the C-terminal intracellular portion of the protein, involved amino acids with similar characteristics, and was found in homozygous state in 1 healthy Japanese individual. Both substitutions were found in heterozygous state in the 2 parents and a healthy brother.
Megarbane et al. (1999) reported a 1-year-old Lebanese girl, born of second-cousin parents, who had clinical features suggesting diastrophic dysplasia (222600) but with unusual radiographic features, including severe platyspondyly, wide metaphyses, and fibular overgrowth, which were partially reminiscent of metatropic dysplasia (see 156550). Molecular analysis of the DTD gene (SLC26A2) revealed homozygosity for a l1388A-C transversion in exon 2, leading to a gln454-to-pro (Q454P) substitution in the tenth transmembrane domain.
Megarbane et al. (2002) reported an aborted female fetus, the third child in the Lebanese family, presenting with almost the same clinical features as those observed in the girl reported by Megarbane et al. (1999). As marked variability within a sibship had been previously reported (Horton et al., 1978; Hall, 1996), this was thought to account for the first affected baby of the family. The birth of a second, identically affected sib, suggested that this represents a distinctive form of the DTDST chondrodysplasia that presents a clinical variant between a mild form of atelosteogenesis type II (256050) and a severe form of diastrophic dysplasia.
Hastbacka et al. (1999) identified the founder mutation underlying the high frequency of diastrophic dysplasia (DTD; 222600) in Finland: a GT-to-GC transition in the splice donor site of the previously undescribed 5-prime untranslated exon of the DTDST gene.
In 7 Finnish individuals with diastrophic dysplasia, Bonafe et al. (2008) found compound heterozygosity for the common Finnish mutation, IVS1+2T-C, and the T512K mutation (606718.0013).
Makitie et al. (2003) identified a homozygous cys653-to-ser (C653S) mutation in 3 patients with early childhood-onset hip dysplasia, recurrent patella dislocation, and normal stature (EDM4; 226900). Abnormal patella ossification was characteristic.
For discussion of the 1-bp deletion of cytosine-418 in the SLC26A2 gene that was found in compound heterozygous state in a patient with atelosteogenesis type II (AO2; 256050) by Rossi et al. (1996), see 606718.0002.
In affected members of the original family with de la Chapelle dysplasia (DLCD; see 256050) (de la Chapelle et al., 1972), Bonafe et al. (2008) identified a homozygous 1535C-A transversion in the SLC26A2 gene, resulting in a thr512-to-lys (T512K) substitution in the sixth cytoplasmic domain. In 7 Finnish individuals with diastrophic dysplasia (DTD; 222600), Bonafe et al. (2008) found compound heterozygosity for the T512K mutation and the common Finnish mutation (606718.0010). In vitro functional expression studies in Chinese hamster ovary cells showed that the T512K-mutant protein had no sulfate uptake. The T512K mutation was not identified in 200 unrelated Finnish controls and 150 non-Finnish Caucasian controls.
In a girl with features suggesting diastrophic dysplasia (DTD; 222600) but with other features usually observed in Desbuquois dysplasia (251450), such as neonatal scoliosis, flat acetabular roof, and proximal femur monkey wrench configuration (which was present in early but not later radiographs), Panzer et al. (2008) identified compound heterozygosity for mutations in the SLC26A2 gene: the common R178X mutation (606718.0005) and a novel A133V mutation. Panzer et al. (2008) noted that the A133V mutation occurs at a boundary between one of the transmembrane and extracellular regions and that the changed amino acid remains hydrophobic and fairly small. They suggested that the A133V substitution is likely to create only a subtle effect on the functionality of the protein.
For discussion of the c.1565C-T transition (c.1565C-T, NM_00112.3) in the SLC26A2 gene, resulting in a ser522-to-phe (S522F) substitution, that was found in compound heterozygous state in a patient with multiple epiphyseal dysplasia-4 (EDM4; 226900) by Barreda-Bonis et al. (2018), see 606718.0002.
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