Alternative titles; symbols
HGNC Approved Gene Symbol: NR0B1
SNOMEDCT: 93235007;
Cytogenetic location: Xp21.2 Genomic coordinates (GRCh38): X:30,304,206-30,309,390 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp21.2 | 46XY sex reversal 2, dosage-sensitive | 300018 | X-linked | 3 |
| Adrenal hypoplasia, congenital | 300200 | X-linked recessive | 3 |
NR0B1 (DAX1) is an orphan member of the nuclear receptor (NR) superfamily. It functions in the proper formation of the adult adrenal gland. NR0B1 has a unique role as an NR in that it acts as a coregulatory protein that inhibits the transcriptional activity of other NRs (review by Niakan and McCabe, 2005).
By identifying ESTs from the dosage-sensitive sex reversal (DSS; 300018)-congenital adrenal hypoplasia (AHC; 300200) critical region, Zanaria et al. (1994) screened human adult testis and human fetal adrenal cDNA libraries and isolated the NR0B1 gene, which they designated DAX1. The DAX1 gene encodes a deduced 470-amino acid protein that belongs to the nuclear hormone receptor superfamily and displays a novel DNA-binding domain at the N terminus. The C terminus shows characteristics of a nuclear hormone receptor ligand-binding domain. Highly significant similarity was found between the C-terminal half of DAX1 and the ligand-binding domain (domain E) of the retinoid X receptor subfamily (e.g., RXRG; 180247). Northern blot analysis detected a 1.9-kb DAX1 mRNA in adult testis and adrenal tissue. Zoo blots showed homologous fragments in all species tested, including chicken, but not in Drosophila melanogaster. Dosage analysis suggested that the cross-hybridizing fragments in mammals are X-linked.
By Northern blot analysis, Guo et al. (1995) found that DAX1 was expressed in the hypothalamus and pituitary, in addition to the gonads and adrenal cortex.
Guo et al. (1996) cloned Ahch, the mouse homolog of DAX1. They noted that the cysteine residues of the putative zinc finger DNA-binding region of DAX1 are conserved in Ahch, suggesting that this region is functional. Swain et al. (1996) isolated the mouse Dax1 gene and found that the coding sequences of human and mouse DAX1 are more similar at the DNA than at the protein levels, suggesting rapid evolution.
By 3-prime RACE of a testis cDNA library, Hossain et al. (2004) cloned a splice variant of DAX1 that they called DAX1-alpha. The deduced 401-amino acid DAX1-alpha protein is identical to DAX1 for the first 389 amino acids, including 3.5 repeats of a 65- to 67-amino acid sequence rich in alanine and glycine. However, DAX1-alpha has a unique 12-amino acid C terminus instead of the transcriptional repression domain of DAX1. RT-PCR showed highest expression of DAX1-alpha in adult testis, followed by fetal kidney and adult adrenal gland, brain, pancreas, ovary, breast, and thymus, with low expression in all other adult tissues examined. DAX1 showed highest expression in adult testis, with much lower levels in fetal kidney and adult adrenal gland, brain, ovary, and pancreas, and no expression in all other tissues examined. Real-time RT-PCR showed that DAX1-alpha predominated in all tissues tested except testis, where DAX1 predominated. Western blot analysis using an antibody directed to the common N terminus of DAX1 and DAX1-alpha detected high levels of both proteins in testis and much weaker expression of DAX1-alpha only in breast.
Ho et al. (2004) identified a DAX1 splice variant similar to DAX1-alpha that they called DAX1A. The deduced 400-amino acid DAX1A protein is identical to DAX1 over the first 389 amino acids. DAX1A differs at its C-terminal end from the DAX1-alpha protein reported by Hossain et al. (2004). RT-PCR detected highest DAX1A expression in testis, ovary, and adrenal gland, with weaker expression in pancreas. DAX1 showed highest expression in lung, pancreas, testis, ovary, and adrenal gland, with weaker expression in brain, spleen, thymus, prostate, and small intestine. Database analysis suggested the presence of DAX1A in chimpanzee, but not in rodent or chicken.
Iyer et al. (2006) stated that each of the 3 full-length N-terminal repeats in DAX1 contains LxxLL nuclear receptor boxes. The C terminus of DAX1 contains a transcriptional silencing domain and an activation factor (AF)-2 domain, and these are absent in DAX1A.
Using immunohistochemistry in rats to analyze NR0B1 expression during steroidogenesis and spermatogenesis, Kojima et al. (2006) observed strong expression in both Leydig and Sertoli cells. The intensity of expression was the same at all 14 cyclical stages of spermatogenesis in 7-day- and 21-day-old rats, but showed a stage-specific pattern in the 56-day-old sexually mature rat, with peak immunostaining during spermatogenesis stages VII to XII, coinciding with stages of major events in spermatogenesis. In humans, quantitative RT-PCR and Western blot analysis of testicular tissue obtained from males at ages ranging from 1 year to 26 years showed increased expression with increasing age during testicular development. In pubertal and adult testes, NR0B1 was abundantly expressed in the nuclei of Sertoli cells, but only a few Leydig cells were faintly NR0B1-positive. Kojima et al. (2006) concluded that expression of NR0B1 is developmentally regulated, with maximal expression during puberty and high expression after puberty.
Using Western blot analysis, Kang et al. (2015) detected Dax1 expression in testis, adrenal gland, placenta, and ovary of cynomolgus monkey. Dax1 expression was absent in heart, liver, spleen, lung, kidney, skeletal muscle, small intestine, brain, and uterus.
Zanaria et al. (1994) and Guo et al. (1996) determined that the DAX1 gene contains 2 exons.
Independently, Hossain et al. (2004) and Ho et al. (2004) identified an alternatively spliced exon, which they called exon 2-alpha or 2A, respectively, between NR0B1 exons 1 and 2.
Zanaria et al. (1994) identified the DAX1 gene within the DSS/AHC critical region on the X chromosome. Guo et al. (1996) found tight linkage between the mouse Ahch, glycerol kinase (300474), and dystrophin (300377) genes, thus showing that this region is syntenic with the homologous region of the human X chromosome.
Zanaria et al. (1994) found that the DAX1 protein is an unusual member of the nuclear hormone-receptor superfamily and acts as a dominant-negative regulator of transcription mediated by the retinoic acid receptor. The DAX1 protein is localized mainly in the nucleus and can bind to an RA responsive element (RARE).
Swain et al. (1996) found that the mouse Dax1 gene is expressed in the first stages of gonadal and adrenal differentiation and in the developing hypothalamus. Moreover, Dax1 expression is downregulated coincident with overt differentiation in the testis, but persists in the developing ovary. They suggested that these results provided a basis for adrenal insufficiency and hypogonadotropic hypogonadism in males affected by congenital adrenal hypoplasia and were consistent with a role for DAX1 in gonadal sex determination.
Tamai et al. (1996) demonstrated that DAX1 is expressed in the Sertoli cells of rat testis. This expression is regulated during spermatogenesis and peaks during the androgen-sensitive phase of the spermatogenic cycle. They also found that DAX1 expression in Sertoli cells is regulated developmentally. Maximum levels are present in the rat between postnatal days 20 and 30, during the first spermatogenic wave. Furthermore, activation of the cAMP-signaling pathway by follicle-stimulating hormone (FSH; see 136530) causes downregulation of DAX1 expression in cultured Sertoli cells. These data indicated that DAX1 expression in Sertoli cells may influence the development of spermatogenic cells in response to steroid and pituitary hormones.
Binding sites for the DAX1 protein are found in the promoters of the DAX1 and steroidogenic acute regulatory protein (STAR; 600617) genes. Zazopoulos et al. (1997) showed that DAX1 binds DNA and acts as a powerful transcriptional repressor of STAR gene expression, leading to a drastic decrease in steroid production. They provided in vitro and in vivo evidence that DAX1 binds to DNA hairpin structures. The results established that DAX1 is the first member of the nuclear receptor superfamily with novel DNA-binding features. They showed that it has regulatory properties critical to the understanding of its physiologic functions.
The finding of Muscatelli et al. (1994) that point mutations in the DAX1 gene cause AHC and HHG (see MOLECULAR GENETICS) strongly suggested that DAX1 is essential for the development of a functioning hypothalamus-pituitary-gonadal axis. The authors noted that, in mice, disruption of the Ftz-F1 autosomal gene, which encodes the nuclear hormone receptor SF1 (NR5A1; 184757), prevents the development of adrenal glands and gonads (Luo et al., 1994). In the human male, disruption of DAX1 does not prevent the initial stages of gonadal development, but the adrenal does not differentiate beyond the fetal stage. Achermann et al. (1999) found that mutation in the human NR5A1 gene results in XY sex reversal with adrenal failure.
DAX1 binds to hairpin secondary structures and blocks steroidogenesis in adrenal cells by transcriptional repression of the STAR promoter. Lalli et al. (1997) investigated the molecular mechanism of this repression. They found that the DAX1 C terminus contains transcriptional silencing activity, which can be transferred to a heterologous DNA-binding domain. Two cooperating domains are required for the silencing function, one located within helix H3 and the other within H12. The silencing function is cell- and promoter-specific. By confocal and immunogold electron microscopy, Lalli et al. (2000) showed that DAX1 is localized in both the cytoplasm and nucleus of human adrenal cortex and mouse Leydig tumor cells. Much of the DAX1 is associated with polyribosomes in complexes with polyadenylated RNA. The 3 N-terminal repeats act cooperatively to direct DAX1 binding to RNA, and the C-terminal ligand-binding domain (LBD) also functions as an autonomous RNA-binding domain.
Reincke et al. (1998) investigated the expression of DAX1 in a variety of adrenocortical tumors and compared the results with STAR mRNA expression. They found low or absent DAX1 expression in aldosterone-producing adenomas and in aldosterone-producing adrenocortical carcinomas. Cortisol-producing adenomas showed intermediate DAX1 expression (n = 8; 92 +/- 16%), as did 3 non-aldosterone-producing carcinomas (72%, 132%, and 132%). High DAX1 expression was present in nonfunctional adenomas (n = 3; 160 +/- 17%). In contrast to DAX1, STAR mRNA expression did not show significant variations between groups. Reincke et al. (1998) concluded that high DAX1 expression in adrenocortical tumors is associated with a nonfunctional phenotype, whereas low DAX1 expression favors mineralocorticoid secretion, and that these effects on steroidogenesis are mediated by mechanisms other than repression of STAR gene expression. They suggested that DAX1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.
XY individuals carrying duplications of Xp21 undergo sex reversal and develop as females. Swain et al. (1998) noted that XY mice carrying extra copies of Dax1 as a transgene show delayed testis development when the gene is expressed at high levels, but do not normally show sex reversal. Swain et al. (1998) found that complete sex reversal occurred, however, when the transgene was tested against weak alleles of the sex-determining Y-chromosome gene Sry (480000). These results showed that Dax1 is largely, if not solely, responsible for dosage-sensitive sex reversal and provided a model for early events in mammalian sex determination, when precise levels and timing of gene expression are critical. The results of Swain et al. (1998) indicated that Dax1 functions as an anti-testis gene by acting antagonistically to Sry. The orphan nuclear receptor Dax1 was originally proposed to act as an 'anti-testis' factor. In studies in the mouse, however, Meeks et al. (2003) found that Nr0b1 is in fact required for testis differentiation. Sex reversal in the absence of Dax1 occurred after normal expression of Sry, suggesting that Sry and Dax1 are both required for normal testis determination.
Nachtigal et al. (1998) showed that WT1(-KTS) (607102) isoforms associated and synergized with SF1 (184757) to promote mullerian inhibiting substance (MIS, or AMH; 600957) expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (194080), failed to synergize with SF1. DAX1 antagonized synergy between SF1 and WT1, most likely through a direct interaction with SF1. Nachtigal et al. (1998) proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation.
By coexpression in HeLa cells, Hossain et al. (2004) confirmed that DAX1 repressed SF1-mediated expression of reporter gene driven by the STAR promoter. DAX1-alpha relieved this repression in a dose-dependent manner. Similar results were obtained with a reporter construct containing the CYP17 (CYP17A1; 609300) promoter. Like DAX1, in vitro-translated DAX1-alpha bound a hairpin DNA structure in the STAR promoter. SF1 coprecipitated with both DAX1 and DAX1-alpha, but only DAX1 bound the promoter region of Alien (COPS2; 604508). Hossain et al. (2004) concluded that DAX1-alpha antagonizes the transcriptional repression activity of DAX1.
Using a yeast 2-hybrid system and transfected HEK293 cells, Iyer et al. (2006) showed that DAX1 homodimerized. In HEK293 cells, homodimers were detected in both the nucleus and cytoplasm, and the homodimers dissociated upon heterodimerization with SF1 or ligand-activated ER-alpha (ESR1; 133430). Homodimerization of DAX1 appeared to be mediated by antiparallel interaction between its N-terminal LxxLL motifs and C-terminal AF2 domain. SHP (NR0B2; 604630) formed a similar antiparallel homodimer via its N-terminal LxxLL motifs and C-terminal AF2 domain, and DAX1 could form a heterodimer with SHP and also with DAX1A.
Iyer et al. (2007) showed that the DAX1-DAX1A interaction was mediated by the LxxLL domain of DAX1A and the AF2 domain of DAX1. DAX1A localized predominantly to the cytoplasm, whereas DAX1-DAX1A heterodimers localized to the nucleus, suggesting different functions for DAX1A in each compartment.
Kojima et al. (2006) analyzed expression levels of NR0B1 mRNA in testicular tissue from 22 patients with nonobstructive azoospermia and detected NR0B1 in all specimens. Quantitative RT-PCR showed no significant relationship between the expression level of NR0B1 and serum testosterone concentration. However, the average expression levels of NR0B1 mRNA were significantly lower in patients with maturation arrest and Sertoli cell-only syndrome compared to patients with hypospermatogenesis or men with normal spermatogenesis and obstructive azoospermia, suggesting that the function of NR0B1 in Sertoli cells is required for normal spermatogenesis and fertility.
Reviews
Niakan and McCabe (2005) reviewed the origin and function of DAX1 in human and mouse.
Congenital Adrenal Hypoplasia
Muscatelli et al. (1994) demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism (AHC; 300200). In 6 patients with AHC and 12 patients who had AHC with glycerol kinase deficiency (GKD; 307030) or AHC-GKD with Duchenne muscular dystrophy (DMD) (see chromosome Xp21 deletion syndrome, 300679), DAX1 was deleted. In 11 AHC families, and 1 sporadic case, point mutations were found in the coding region of the DAX1 gene (see, e.g., 300473.0001-300473.0005). All AHC patients over 14 years of age and with only point mutations in DAX1 were also found to have hypogonadotropic hypogonadism, confirming that the DAX1 gene is responsible for both findings. However, in 4 sporadic cases and a single familial case of AHC, no point mutations were found, suggesting genetic heterogeneity.
Guo et al. (1996) used SSCP analysis to identify 3 new DAX1 gene mutations as well as polymorphisms that may permit linkage analysis in families without identified mutations.
Adrenal hypoplasia typically presents as adrenal insufficiency during infancy, whereas hypogonadotropic hypogonadism becomes evident in affected males who survive into childhood and approach puberty. Habiby et al. (1996) identified mutations in the DAX1 gene in 2 affected members of 2 kindreds. Studies of baseline levels of luteinizing hormone (152780), FSHB (136530), and chorionic gonadotropin alpha (CGA; 118850) demonstrated differences between the 2 families and suggested to Habiby et al. (1996) that DAX1 mutations impair gonadotropin production by acting at both the hypothalamic and pituitary levels. McCabe (1996) agreed with these conclusions, noting that loss of DAX1 results in adrenal hypoplasia and hypogonadotropic hypogonadism, and increased DAX1 leads to dosage-sensitive sex reversal and a female phenotype or ambiguous genitalia in XY-genotypic males.
Zhang et al. (1998) identified 14 new mutations in 17 families with AHC, bringing the total number of families with AHC studied to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and 6 missense mutations, and 1 single-codon deletion. They mapped 7 single amino acid changes to a homology model constructed by use of the 3-dimensional crystal structure of the thyroid hormone receptor (190160) and retinoid X receptor-alpha (180245). All single amino acid changes mapped to the C-terminal half of the DAX1 protein in the conserved hydrophobic core of the putative ligand-binding domain, and no affected residue was expected to interact directly with a ligand. Zhang et al. (1998) concluded that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculated that the codon deletion and missense mutations give insight into the structure and function of DAX1.
Peter et al. (1998) studied 18 AHC boys from 16 families: 4 with AHC, GKD, and DMD; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most presented as neonates with salt wasting and hyperpigmentation. Aldosterone deficiency usually preceded cortisol deficiency, which explained why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. In samples from the 15 patients studied by molecular analysis of the DAX1 gene, large deletions were found in 6 patients, and point mutations in another 7. All of the point mutations identified encoded a nonfunctional, truncated DAX1 protein. Two brothers with primary adrenal insufficiency and histories strongly suggesting AHC had no mutation in the DAX1 gene, suggesting genetic heterogeneity for the disorder.
Merke et al. (1999) studied a family in which 2 males had a nonsense mutation in the DAX1 gene as the cause of congenital adrenal hypoplasia with gonadotropic hypogonadism. Their unaffected mother was heterozygous and their unaffected maternal grandfather was hemizygous for the nonsense mutation; the authors stated that the latter findings indicated a lack of penetrance of the mutation. The results of mutation analysis of DNA from urinary sediment were similar to those in leukocyte DNA. A maternal aunt, who had isolated hypogonadotropic hypogonadism, was homozygous for the mutation. This homozygosity was thought to have resulted from gene conversion, the nonreciprocal transfer of DNA from one parental allele to the other. This is a novel suggestion for manifestations in heterozygous females.
Phelan and McCabe (2001) presented a compendium of published NR0B1 mutations and polymorphisms, and discussed them in the context of known biology and clinical applicability.
Lehmann et al. (2002) noted that all known DAX1 mutations found in AHC patients alter the C terminus of the protein, which shares similarity to the ligand-binding domain of nuclear hormone receptors and bears transcriptional repressor activity. This property is invariably impaired in DAX1 AHC mutants. Lehmann et al. (2002) showed that the localization of DAX1 AHC mutant proteins is drastically shifted toward the cytoplasm, even if their nuclear localization signal, which resides in the N-terminal region of the protein, is intact. Cytoplasmic localization of DAX1 AHC mutants correlates with an impairment in their transcriptional repression activity. These results revealed a critical role of an intact C terminus in determining DAX1 subcellular localization and constituted an important example of a defect in human organogenesis caused by impaired nuclear localization of a transcription factor.
Lehmann et al. (2003) showed that several DAX1 AHC mutants had a misfolded conformation, which correlated with their cytoplasmic retention. Extensive structure-function analysis revealed that the chemical nature of amino acid residues at positions interrupted by AHC mutations and critical determinants in helix 12 affected DAX1 nuclear localization and transcriptional silencing. Mutations in a conserved putative corepressor binding surface had a negative effect upon DAX1 transcriptional repression only when they also affected protein expression levels. Lehmann et al. (2003) suggested that a folding defect underlies the impaired function of DAX1 missense mutants found in AHC/HHG patients, and that interactions with transcriptional cofactors different from known corepressors mediate DAX1 silencing properties.
In 3 male relatives with adrenal phenotypes ranging from adrenal crisis in infancy to asymptomatic adrenal insufficiency, Raffin-Sanson et al. (2013) identified a trp39-to-ter mutation in NR0B1 (W39X; 300473.0031).
46,XY Sex Reversal
Bardoni et al. (1994) studied 8 patients with duplications at chromosome Xp21, including 4 who had 46,XY sex reversal (SRXY2; 300018) and 4 who were 46,XY phenotypic males. Breakpoint analysis identified an approximately 20-Mb region on Xp21.2-p22.1 that was duplicated only in the 46,XY females. Further analysis involving 1 additional 46,XY sex-reversed patient with a submicroscopic duplication on Xp defined a 160-kb critical region adjacent to the congenital adrenal hypoplasia locus (AHC; 300200) that was exclusively duplicated in the patients with male-to-female sex reversal; the authors designated the locus DSS for 'dosage-sensitive sex reversal' (see 300473.0014).
Associations Pending Confirmation
For discussion of a possible association between mutation in the NR0B1 gene and a form of AHC involving isolated mineralocorticoid deficiency, see 300473.0030.
Exclusion of DAX1 Mutations
Telvi et al. (1996) reported GTD associated with mental retardation, facial dysmorphism, and hypoplastic external genitalia in an 18-year-old male with familial duplication of the segment Xp22.32-p22.11. Molecular analysis showed that the DAX1 gene was not involved in this duplication. Two sisters with the same inv dup(Xp) chromosome had short stature but were otherwise phenotypically normal. The abnormal X chromosome was late replicating in 96 to 98% of cells from the sisters. The authors discussed several possible explanations for the proband's phenotype.
Achermann et al. (1999) hypothesized that DAX1 might be a candidate gene in patients with idiopathic sporadic or familial HHG or constitutional delay of puberty. They performed direct sequencing of the DAX1 gene in 106 patients, including 85 (80 men and 5 women) with sporadic HHG or constitutional delay of puberty and patients from 21 kindreds with familial forms of these disorders. No DAX1 mutations were found in these groups of patients, although silent single nucleotide polymorphisms were identified. The authors concluded that mutations in DAX1 are unlikely to be a common cause of HHG or pubertal delay in the absence of a concomitant history of adrenal insufficiency.
Calvo et al. (2001) used heteroduplex analysis to screen the genes encoding STAR, SF1, DAX1, and CYP11A (118485) for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. Analysis of DAX1 showed no variant in any of the women studied. The authors concluded that mutations in STAR, SF1, CYP11A, and DAX1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities found in these women.
Lin et al. (2006) studied the prevalence of DAX1 and SF1 mutations in 117 children and adults with primary adrenal failure of unknown etiology (i.e., not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease). DAX1 mutations were found in 58% (37 of 64) of 46,XY phenotypic boys referred with adrenal hypoplasia and in all boys (8 of 8) with hypogonadotropic hypogonadism and a family history suggestive of adrenal failure in males. SF1 mutations causing adrenal failure were found in only 2 patients with 46,XY gonadal dysgenesis. No DAX1 or SF1 mutations were identified in the adult-onset group. Lin et al. (2006) concluded that DAX1 mutations are a relatively frequent cause of adrenal failure in this group of boys, whereas SF1 mutations causing adrenal failure in humans are rare and are more likely to be associated with significant underandrogenization and gonadal dysfunction in 46,XY individuals.
In the mouse, Yu et al. (1998) disrupted the Ahch gene to generate a mouse model of congenital adrenal hypoplasia with hypogonadotropic hypogonadism that allowed the function of Ahch to be examined in both males and females. Though Ahch had been postulated to function as an ovarian determination gene, the loss of Ahch function in females did not affect ovarian development or fertility. Instead, Ahch was essential for the maintenance of spermatogenesis. Lack of Ahch caused progressive degeneration of the testicular germinal epithelium independent of abnormalities in gonadotropin and testosterone production and resulted in male sterility.
Kang et al. (2015) used CRISPR/Cas9 genome engineering to mutate Dax1 in cynomolgus monkey. They obtained no live offspring with Dax1 mutations following embryo transfer, but several fetuses showed extensive Dax1 modifications, including a male fetus with targeted mutations in Dax1 in most somatic tissues and gonad. Testis of the Dax1-deficient fetus was grossly normal, but it had altered ultrastructural morphology and expansion of blood vessels. Absence of Dax1 did not alter Sertoli cell fate, testis cords were well organized, and tubular structure remained intact, but with reduced number of germ cells. Dax1-deficient testis showed normal expression of Amh, Sox9 (608160), and Wt1, but expression of the Wnt signaling protein beta-catenin (CTNNB1; 116806) was upregulated in interstitial cells, as was Vegf (VEGFA; 192240) content. Adrenal gland of the Dax1-deficient fetus showed substantial enlargement of the fetal zone. Dax1 deficiency did not cause any apparent defects in other tissues or organs.
In a 44-year-old man who had AHC with hypogonadotropic hypogonadism (300200), Muscatelli et al. (1994) identified a nonsense mutation in the NR0B1 gene involving gln283 (Q283X) and leading to suppression of a PvuII site. Age at onset of the disorder was 10 days of life.
In a patient with AHC (300200) and bilateral cryptorchidism, Muscatelli et al. (1994) identified a W369X nonsense mutation in the NR0B1 gene. Age at onset of the disorder was 17 days of life.
In a patient who had AHC with hypogonadotropic hypogonadism (300200), Muscatelli et al. (1994) identified a L263X nonsense mutation in the NR0B1 gene, which created a BstUI site. Age of AHC onset was 8 days of life, and age of HHG onset was before 14 years.
In 2 brothers with AHC with hypogonadotropic hypogonadism (300200), Muscatelli et al. (1994) identified a 1034G-A transition in the NR0B1 gene, which was predicted to generate an arg267-to-pro (R267P) substitution, and resulted in suppression of a CfoI site.
Lalli et al. (1997) found that 2 mutations in the DAX1 gene, R267P and deletion of V269, impair transcriptional silencing of the STAR promoter, suggesting that loss of the functional repression plays a role in the pathogenesis of AHC. (See also Lalli et al. (2000) and 300473.0008).
In a male patient who had AHC with hypogonadotropic hypogonadism (300200), Muscatelli et al. (1994) observed a G-to-A transition in the NR0B1 gene, resulting in a nonsense mutation at codon 235 (trp235-to-ter; W235X), creating a MaeI restriction site.
In a Japanese male patient, originally reported at 17 years of age by Takayanagi et al. (1992), who had AHC with hypogonadotropic hypogonadism (300200) and whose brother and 2 maternal uncles had died in infancy or early childhood of hypovolemic shock, Yanase et al. (1996) found a G-to-A transition in the NR0B1 gene, resulting in a nonsense mutation at codon 171 (trp171-to-ter; W171X).
In a 20-year-old Japanese man who had an apparently sporadic case of AHC with hypogonadotropic hypogonadism (300200), Yanase et al. (1996) identified a 1-bp deletion (delT) in codon 280, leading to a frameshift and a premature stop at codon 371. The mutation created a new MspI restriction site which was absent in the PCR products of both parents.
In 5 male patients with AHC (300200) from the Greenlandic family originally reported by Petersen et al. (1982), Schwartz et al. (1997) identified a 1553A-T transversion in the NR0B1 gene, resulting in an asn440-to-ile (N440I) substitution. The substitution represented change from a polar amino acid to a nonpolar amino acid. Both patients who had reached the age of puberty exhibited hypogonadotropic hypogonadism. The authors noted that among 33 female relatives at risk for the mutation, they identified 10 as carriers and excluded 23 from being carriers, information important for genetic counseling.
Lalli et al. (2000) determined that the N440I mutation results in impaired RNA-binding activity of the DAX1 protein (see also Lalli et al., 1997 and 300473.0004).
Nakae et al. (1996) characterized the DAX1 gene from 6 patients, including 2 sibs, with AHC (300200), and found 5 novel mutations including 3 nonsense and 2 frameshift mutations. The nonsense mutations were a C-to-T transition (gln395-to-ter; Q395X), a C-to-G transversion (tyr271-to-ter; Y271X; 300473.0010), and a C-to-A transversion (tyr91-to-ter; Y91X; 300473.0011). The Y91X mutation was found in 2 sibs. The frameshift mutations were a 2-bp deletion (1610delAT) and a 1-bp (G) insertion resulting in a premature stop at codon 462 (300473.0012), and a 1-bp deletion (1169delC), resulting in a frameshift which caused a premature stop codon at position 371 (300473.0013). A 21-year-old male patient in whom the Q395X mutation was identified had hypogonadotropic hypogonadism; the other 5 patients were prepubertal. All mutated NR0B1 proteins had truncated C-terminal domains, suggesting that these 5 mutations cause AHC and that the C terminus of the DAX1 protein, especially the terminal 11 amino acids, is necessary for normal adrenal cortical embryogenesis.
See 300473.0009 and Nakae et al. (1996).
See 300473.0009 and Nakae et al. (1996).
See 300473.0009 and Nakae et al. (1996).
See 300473.0009 and Nakae et al. (1996).
XY individuals with a duplication of part of the short arm of the X chromosome and an intact SRY gene show male-to-female sex reversal (SRXY2; 300018). The single X chromosome in these individuals does not undergo X-chromosome inactivation; therefore, these individuals presumably carry 2 active copies of genes, including the NR0B1 gene, in the duplicated region. Individuals with deletion of this region develop as males. Genes within the DSS region are, therefore, not essential for testis development, but, when present in a double dose, interfere with testis formation (Swain et al., 1998).
Nakae et al. (1997) characterized the NR0B1 gene from 7 patients in 6 kindreds with AHC (300200) and identified 1 frameshift mutation, 2 missense mutations (see 300473.0016 and 300473.0017), and 3 deletion mutations (see 300473.0018) in the NR0B1 gene. The frameshift mutation, found in a 26-year-old male patient who had AHC with hypogonadotropic hypogonadism, was a 2-bp deletion (388delAG) resulting in a premature stop codon at position 70.
In a 15-year-old male patient who had AHC with hypogonadotropic hypogonadism (300200), Nakae et al. (1997) identified a 1380G-T transversion in the NR0B1 gene, resulting in a lys382-to-asn (L382N) substitution. Lys382 is highly conserved among other related orphan nuclear receptor superfamily members.
In a pair of prepubertal sibs with AHC (300200), Nakae et al. (1997) identified a 1107G-C transversion in the NR0B1 gene, resulting in a trp291-to-cys (W291C) substitution. Trp291 is highly conserved among other related orphan nuclear receptor superfamily members.
By Southern blotting and PCR of a GGAA tetranucleotide tandem repeat, Nakae et al. (1997) detected deletions in the NR0B1 gene of 3 unrelated prepubertal patients with AHC (300200). The extents of the deletions were not determined. In 2 of the patients, the deletion was familial; in the third, it was de novo.
In a 42-year-old patient who had congenital adrenal hypoplasia with hypogonadotropic hypogonadism (300200), Wang et al. (1999) identified a 4-bp deletion (1464delACTC) in the second exon of the NR0B1 sequence, which caused a frameshift and predicted a premature stop codon at amino acid 416. The diagnosis of AHC and HHG had been made at 2 weeks of age when he presented to the Hospital for Sick Children in Toronto with vomiting, loose stools, and failure to thrive. He was treated with intramuscular deoxycortisone acetate (DOCA) and discharged with 2 subcutaneous DOCA pellets. Prednisone was started with added salt at the age of 23 months. He had been maintained on glucocorticoids since that time. At age 15 he developed a slipped left femoral epiphysis, which was treated surgically. His bone age at that time was 11 years. He had no secondary sexual development when studied at the age of 17 years and was started on testosterone. No other family members were affected.
In a man who presented with apparently isolated adrenal insufficiency at 28 years of age, later confirmed as AHC (300200), Tabarin et al. (2000) found a missense mutation, ile439-to-ser (I439S), in the DAX1 gene. Physical examination revealed partial pubertal development and undiagnosed incomplete hypogonadotropic hypogonadism. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. The patient's complaint was fatigue for 5 years. During the year before study, the patient noted additional symptoms, such as episodes of nausea, abdominal pain, orthostatic dizziness, and loss of 4.5 kg of body weight. His height and weight were 171 cm and 58 kg, respectively, and his blood pressure was 100/60 mm Hg while supine. On physical examination, moderate and diffuse increased skin pigmentation was noted, with a few hyperpigmented macules on the lips. Facial, thoracic, and pubic hair (Tanner stage 3) were sparse, with a gynecoid distribution of subcutaneous fat. There was no gynecomastia. Penile length was normal, but testicular volume was low (6 ml bilaterally). The patient stated that puberty had occurred at the age of approximately 16. He described impaired libido and infrequent erections.
Tabarin et al. (2000) studied the mutant I439S protein for its ability to function as a transcriptional repressor of target genes. Consistent with the patient's mild clinical phenotype, the I439S mutation conferred intermediate levels of repressor activity of DAX1 when compared with mutations associated with classic AHC. This unique case extended the clinical spectrum of AHC to include delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. In accordance with findings in Ahch(Dax1) knockout mice, the clinical features in this patient suggested that DAX1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.
Caron et al. (1999) studied a 20-year-old male patient who had congenital adrenal hypoplasia with hypogonadotropic hypogonadism (300200) due to an 825C-A transversion in the NR0B1 gene, resulting in a tyr197-to-ter (Y197X) substitution. The same mutation was detected in the patient's affected first cousin and in heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2.5 years, bilateral cryptorchidism corrected surgically at the age of 12 years, and failure of spontaneous puberty. Plasma testosterone was undetectable and gonadotropin levels were low and not stimulated after intravenous injection of 100 microg gonadotropin-releasing hormone (GNRH; see 152760). The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. The authors concluded that the hypogonadism was due to a combined hypothalamic-pituitary-gonadal defect and implied that the NR0B1 gene may play a critical role in human testicular function.
Seminara et al. (1999) studied an extended kindred with adrenal hypoplasia congenita with hypogonadotropic hypogonadism (300200) in which 2 males (the proband and his nephew) were affected with a nucleotide deletion (501delA) in the DAX1 gene. The proband's mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 years, after 7 years of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-year period, the proband remained azoospermic. The proband's mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17-18 years. The authors concluded that (1) affected males with AHC/HHG may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; (2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and (3) although affected individuals display minimal responses to pulsatile gonadotropin-releasing hormone (152760), as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.
Achermann et al. (2000) identified a leu381-to-his (L381H) mutation in the DAX1 gene in 2 brothers who were variably affected with AHC (300200). The older brother presented in the first year of life, whereas the younger brother was asymptomatic and normally pigmented at 8 months of age. Although the younger brother had normal basal adrenal steroid concentrations, dynamic testing revealed that he had impaired adrenal reserves and therefore compensated primary adrenal failure. The mutation changes an amino acid located within the putative ligand-binding domain of the nuclear receptor.
Domenice et al. (2001) reported a 2-year-old Brazilian boy with congenital adrenal hypoplasia (AHC; 300200) and transient precocious puberty who had a 1-bp insertion in exon 1 of the DAX1 gene (430insG), which was predicted to result in a novel frameshift mutation and a premature stop codon at position 71. Initial clinical manifestation was isosexual gonadotropin-independent precocious puberty. The authors concluded that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations.
Mantovani et al. (2002) reported AHC (300200) in a patient who presented with hypogonadotropic hypogonadism at 28 years of age. Although the patient had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and the patient did not achieve fertility after 8 months of treatment with gonadotropins. A novel tyr380-to-asp (Y380D) missense mutation in the DAX1 gene, which caused partial loss of function in transient gene expression assays, was found. The authors concluded that partial loss-of-function mutations in DAX1 can present with HHG and covert adrenal failure in adulthood.
Salvi et al. (2002) reported a patient who was diagnosed with adrenal failure (AHC; 300200) at 6 weeks of age, but who experienced transient recovery of adrenal function of several months' duration later in infancy. He subsequently failed to undergo puberty because of hypogonadotropic hypogonadism of pituitary origin, and he was also diagnosed with schizophrenia in early adulthood. Molecular genetic analyses revealed a complex rearrangement in DAX1, including a 2.2-kb deletion spanning the entire second exon and a small 27-bp insertion. The deletion extended from position 4561 through position 6801, completely eliminating exon 2 of the gene. The putative protein encoded by this mutated gene is 429 amino acids long. The initial 389 residues probably correspond to the wildtype DAX1 sequence, whereas the last 40 amino acids are presumably completely unrelated, being transcribed from the intronic sequence adjacent to exon 1. In vitro functional analyses confirmed the absence of repressor activity exerted by the mutant protein.
In the proband of a 5-generation Scottish kindred, 3 members of which had adrenal hypoplasia (300200), Brown et al. (2003) identified a C-to-A transversion in the second exon of the DAX1 gene that resulted in the change of tyr399 to a premature stop codon (Y399X), which truncates the DAX1 protein by 71 amino acids. Kindred analysis established that the mutation had been inherited from the proband's mother. The proband, his deceased brother, and a maternal cousin were hemizygous for the mutation. The mutation was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin (see 118860); the 35-year-old proband exhibited hypogonadotropic hypogonadism. Immunohistochemical analysis of testicular tissue obtained from the proband's affected sib, who had died from adrenal failure as a neonate, showed normal testicular morphology and expression of DAX1, steroidogenic factor-1 (184757), and anti-mullerian hormone (600957). Transient transfection assays demonstrated that the mutation resulted in a severe loss of DAX1 repressor activity.
In the 34-year-old male proband of an English kindred with adrenal hypoplasia and hypogonadotropic hypogonadism (300200), Brown et al. (2003) identified a T-to-C transition in exon 1 of the DAX1 gene, resulting in a leu297-to-pro amino acid change (L297P). Responsiveness to human chorionic gonadotropin (see 118860) was maintained. Kindred analysis established that the mutation had been inherited from the proband's mother. The L297P mutation occurred within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that the mutation resulted in a severe loss of DAX1 repressor activity.
In a 20-year-old male with an unusual form of congenital adrenal hypoplasia (AHC; 300200) manifest as late-onset adrenal insufficiency and gonadal failure, Ozisik et al. (2003) demonstrated a C-to-T transition in the DAX1 gene that resulted in a gln37-to-ter (Q37X) substitution, predicted to cause severe truncation of the protein. Using a combination of in vitro translation assays and studies of DAX1 expression and function in transfected cells, they demonstrated that, in contrast to more distal mutations leading to a nonfunctional protein, this mutation is associated with a milder phenotype due to the expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine, codon 83). The production of this amino-truncated isoform appears to rescue the classical AHC phenotype, thereby delaying the onset of clinically significant adrenal dysfunction until early adulthood. Ozisik et al. (2003) concluded that this case demonstrated a relatively rare phenomenon by which the clinical severity of an inherited human disease is reduced after alternate translation from a site downstream of a premature stop codon.
This variant, formerly titled ISOLATED MINERALOCORTICOID DEFICIENCY, has been reclassified based on the findings of Verrijn Stuart et al. (2007).
In an 11-year-old prepubertal Dutch boy with a mild form of congenital adrenal hypoplasia (AHC; see 300200) involving prominent hypoaldosteronism without clear evidence of glucocorticoid insufficiency, Verrijn Stuart et al. (2007) identified a G-to-C transversion in the NR0B1 gene, resulting in a trp105-to-cys (W105C) substitution in the N terminus of DAX1. In vitro studies of DAX1 expression and function in transfected cells demonstrated mild loss of both repression and activation functions; structure-function analysis suggested that mutations in the N terminus are compensated by the presence of repeat LXXLL motifs that mediate DAX1 interactions with other proteins. An initial ACTH stimulation test in the proband revealed subnormal cortisol results; however, a second test showed normal cortisol values, and he did not experience adrenal crisis while on mineralocorticoid treatment only. The mutation, which was not found in 100 Dutch controls, was present in the proband's mother and was also detected in 3 asymptomatic male relatives. Verrijn Stuart et al. (2007) suggested that phenotypic heterogeneity might result from the effects of other genes that modify or compensate for NR0B1 function, or that environmental events or exposure to medications might unmask underlying adrenal dysfunction.
In a 32-year-old male proband with adrenal insufficiency (AHC; 300200) who had been referred for infertility, Raffin-Sanson et al. (2013) detected hemizygosity for an A-to-G transition in the NR0B1 gene that resulted in substitution of a termination codon for trp39 (W39X). The mutation was also found in the proband's younger brother and nephew. The proband had been diagnosed with adrenal insufficiency at age 19 years and oligospermia at age 24 years. Biologic and hormonal explorations confirmed primary adrenal insufficiency, and computed tomography showed bilateral adrenal atrophy. Puberty had been spontaneous at age 13 years, with normal virilization, growth spurt, and testicular growth. Plasma total testosterone level remained normal throughout 25 years of follow-up, whereas oligospermia worsened over time. The patient fathered 1 child at age 33 through in vitro fertilization and another 2 years later after spontaneous conception. The proband's brother was normally virilized but had azoospermia and low testosterone; he exhibited an abnormal cortisol response to the standard-dose cortrosyn test, consistent with mild adrenal insufficiency. The proband's nephew had an adrenal crisis during the second week of life. He had normal testes and genitalia, but elevated plasma ACTH and renin levels confirmed primary adrenal insufficiency. Raffin-Sanson et al. (2013) stated that this was the first reported case of long-term preservation of gonadotrope function in a patient with markedly defective spermatogenesis due to an NR0B1 mutation, and concluded that the phenotypes of the proband, his brother, and his nephew illustrate the different possible adrenal consequences of identical NR0B1 mutations.
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