Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked adrenal hypoplasia congenita (AHC) is an inherited disorder of the development of the adrenal cortex. The gene responsible for this genetic disorder has been identified using positional cloning methods and has been named DAX-1 based on its localization within the dosage-sensitive sex reversal (DSS) locus and the AHC locus on the X chromosome. The DAX-1 gene consists of two exons separated by a 3.4 kb intron. Analysis of DNA from patients with deletions in the AHC critical region in the X chromosome provided strong indication for the involvement of the DAX-1 gene in X-linked AHC. A number of intragenic mutations within the DAX-1 gene have also been identified in patients with isolated AHC. The DAX-1 gene product belongs to the nuclear hormone receptor superfamily based on the presence of an entire ligand binding domain present in the carboxy-terminal region of the receptor. However, DAX-1 has a domain structure which is very unusual with respect to other nuclear hormone receptor superfamily members. The amino-terminal portion of DAX-1 contains a novel domain consisting of 3.5 repeats of a 65-67 amino acid motif that contains two putative zinc finger structures in place of the more usual amino-terminal domain, DNA binding domain, and hinge region of the typical nuclear hormone receptors. It has been proposed that the amino-terminal portion of the DAX-1 protein is the DNA binding domain. The expression pattern of DAX-1 suggests that it may play a role in the regulation of steroidogenesis. Not only is DAX-1 expressed in the adrenal glands, but it is also expressed in the ovaries and testes. Most recently, we demonstrated that DAX-1 is also expressed in the hypothalamus and pituitary gland. The expression of DAX-1 in the neuroendocrine system suggests that interruption of the expression in these tissues may be the cause of the hypogonadotropic hypogonadism (HH) that is frequently associated with AHC. Interestingly, hybridization of a human DAX-1 cDNA probe with genomic DNA from various species indicated that a DAX-1 homologue may exist in yeast. Thus, DAX-1 or a DAX-1-like transcription factor may be the most primitive member of the nuclear hormone receptor superfamily. Although the molecular mechanism of action of DAX-1 is not yet characterized, its importance for the development and physiology of the adrenal gland and gonads is indicated by its involvement in AHC and HH. Analysis of the functions of DAX-1 along with its regulation of expression will not only provide information concerning the actions of this new member of the nuclear hormone receptor superfamily, but will also yield insight into the pathogenesis of AHC and HH and may allow for the development of gene therapy protocols for the treatment of these diseases.
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PMID:The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. 870 Oct 82

Ahch (also known as Dax1) encodes a transcription factor that has been implicated in sex determination and gonadal differentiation. Mutations in human AHC cause X-linked, adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH). Duplication of the Xp21 dosage-sensitive sex reversal (DSS) region, which contains the Ahch locus, and transgenic overexpression of Ahch cause male-to-female sex reversal. Using Cre-mediated disruption of Ahch, we have generated a mouse model of AHC-HH that allows the function of Ahch to be examined in both males and females. Although Ahch has been postulated to function as an ovarian determination gene, the loss of Ahch function in females does not affect ovarian development or fertility. Ahch is instead essential for the maintenance of spermatogenesis. Lack of Ahch causes progressive degeneration of the testicular germinal epithelium independent of abnormalities in gonadotropin and testosterone production and results in male sterility. Ahch is thus not an ovarian determining gene, but rather has a critical role in spermatogenesis.
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PMID:Role of Ahch in gonadal development and gametogenesis. 984 95

DAX1 is an unusual member of the orphan nuclear receptor family of transcription factors. Mutations in human DAX1 cause X-linked adrenal hypoplasia congenita, while abnormal duplication of the gene is responsible for male-to-female dosage-sensitive sex reversal. Based on these and other observations, DAX1 is thought to play a role in adrenal and gonadal development in mammals. As DAX1 has not previously been described in any other vertebrate, a putative avian DAX1 clone was isolated from an embryonic chicken (Gallus domesticus) urogenital ridge cDNA library. The expression profile of this cDNA was then examined during gonadogenesis. The clone included the conserved 3' ligand-binding motif identified in humans and mice but the 5' region lacked the repeat motif thought to specify a DNA-binding domain in mammals. Southern blot analysis and fluorescence in situ hybridisation mapping showed that the gene is autosomal, located on chromosome 1q. Sequence comparisons showed that the putative chicken DAX1 protein has 63 and 60% identity with the human and mouse proteins respectively over the region of the conserved ligand-binding domain. However, stronger identity (74%) exists with a putative alligator DAX1 sequence over the same region. Northern blotting detected a single 1.4 kb transcript in late embryonic chicken gonads, while RNase protection assays revealed expression in the embryonic gonads of both sexes during the period of sexual differentiation. Expression increased in both sexes during gonadogenesis, but was higher in females than in males. This is the first description of a DAX1 homologue in a non-mammalian vertebrate.
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PMID:Cloning and expression of a DAX1 homologue in the chicken embryo. 1065 94

Pulsatile GnRH acts at the GnRH receptor on gonadotropes to stimulate gonadotropin gene expression, hormone synthesis and secretion. The pituitary gonadotropins, LH and FSH, stimulate steroid production and gametogenesis in males and in females. Gonadotropin production thus requires the normal development and function of hypothalamic GnRH-producing neurons and pituitary gonadotrope cells. Genes involved in gonadotrope development and/or gene expression include SF1, DAX1, KAL, GNRHR, PC1, HESX1, LHX3, PROP1, LH beta, and FSH beta. Given the complex control of gonadotropin biosynthesis and secretion, it is not surprising that genetic abnormalities have been identified at several of these steps. Some of the mutations that will be reviewed include: (1) SF1 and DAX1-orphan nuclear receptors that are expressed at multiple levels throughout the reproductive axis; (2) KAL-X-linked Kallmann syndrome, where there is abnormal development of hypothalamic GnRH-producing neurons; (3) PC1-causing abnormal processing of GnRH and GNRHR mutations that impair action at the GnRH receptor; (4) HESX1, LHX3, PROP1-abnormal development/function of the gonadotrope cell lineage; (5) LH beta and FSH beta-mutations in the gonadotropin genes that cause structural abnormalities in the hormones. Although all of these gene defects lead to gonadotropin deficiency, each disorder is associated with unique phenotypic or hormonal features. Characterization of the molecular basis of gonadotropin deficiency is useful for directing therapy and for genetic counseling. Identification of these mutations also provides insight into the pathways that govern reproduction.
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PMID:Inherited disorders of the gonadotropin hormones. 1142 Jan 32

DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1] is an orphan nuclear receptor that represses transcription by steroidogenic factor-1 (SF-1), a factor that regulates expression of multiple steroidogenic enzymes and other genes involved in reproduction. Mutations in the human DAX1 gene (also known as AHC) cause the X-linked syndrome AHC, a disorder that is associated with hypogonadotropic hypogonadism also. Characterization of Dax1-deficient male mice revealed primary testicular defects that included Leydig cell hyperplasia (LCH) and progressive degeneration of the germinal epithelium, leading to infertility. In this study, we investigated the effect of Dax1 disruption on the expression profile of various steroidogenic enzyme genes in Leydig cells isolated from Dax1-deficient male mice. Expression of the aromatase (Cyp19) gene, which encodes the enzyme that converts testosterone to estradiol, was increased significantly in the Leydig cells isolated from mutant mice, whereas the expression of other proteins (e.g., StAR and Cyp11a) was not altered. In in vitro transfection studies, DAX-1 repressed the SF-1-mediated transactivation of the Cyp19 promoter but did not inhibit the StAR or Cyp11a promoters. Elevated Cyp19 expression was accompanied by increased intratesticular levels of estradiol. Administration of tamoxifen, a selective estrogen-receptor modulator, restored fertility to the Dax1-deficient male mice and partially corrected LCH, suggesting that estrogen excess contributes to LCH and infertility. Based on these in vivo and in vitro analyses, aromatase seems to be a physiologic target of Dax-1 in Leydig cells, and increased Cyp19 expression may account, in part, for the infertility and LCH in Dax1-deficient mice.
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PMID:Aromatase (Cyp19) expression is up-regulated by targeted disruption of Dax1. 1142 38

SF-1 (steroidogenic factor-1) (NR5A1) and DAX-1 (dosage-sensitive sex-reversal, adrenal hypoplasia congenital, X chromosome) (NR0B1) are orphan nuclear receptors that are expressed in the adrenal gland, gonads, ventromedial hypothalamus (VMH), and pituitary gonadotrope cells. The function of these genes has been clarified by examining the consequences of naturally occurring mutations in humans, as well as targeted disruption of the genes in mice. Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Most DAX1 mutations introduce frameshifts and/or cause premature termination of the protein. Relatively few missense mutations have been described and all are located within the carboxy-terminal half of the protein. Transfection assays demonstrate that AHC-associated DAX1 mutations abrogate its ability to act as a transcriptional repressor of SF-1. Most boys affected with AHC present with adrenal insufficiency in early infancy, although a significant fraction present in later childhood or even as young adults. The degree of gonadotropin deficiency is also variable. With the exception of one mild missense DAX1 mutation, genotype-phenotype correlations have been elusive, suggesting an important role for modifier genes. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Similar abnormalities appear to be present in humans. Targeted mutagenesis of Sf1 (FtzF1) prevents gonadal and adrenal development, and causes male-to-female sex-reversal. A human XY individual with a heterozygous SF1 mutation presented with adrenal insufficiency and complete sex-reversal; this DNA-binding domain mutation prevents SF-1 stimulation of its target genes. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for unraveling the genetic pathways that govern adrenal and gonadal development.
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PMID:Phenotypic spectrum of mutations in DAX-1 and SF-1. 1173 90

Mutations in the DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome; NR0B1] gene cause X-linked AHC associated with hypogonadotropic hypogonadism. DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily, acting as a transcriptional repressor of genes involved in the steroidogenic pathway. All DAX-1 mutations found in AHC patients alter the protein C terminus, which shares similarity to the ligand binding domain of nuclear hormone receptors and bears transcriptional repressor activity. This property is invariably impaired in DAX-1 AHC mutants. Here we show that the localization of DAX-1 AHC mutant proteins is drastically shifted toward the cytoplasm, even if their nuclear localization signal, which resides in the N terminal of the protein, is intact. Cytoplasmic localization of DAX-1 AHC mutants correlates with an impairment in their transcriptional repression activity. These results reveal a critical role of an intact C terminus in determining DAX-1 subcellular localization and constitute an important example of a defect in human organogenesis caused by impaired nuclear localization of a transcription factor.
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PMID:X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein. 1203 80

DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenital (AHC) critical region on the X chromosome, gene 1] is a transcription factor expressed in the adrenal gland and at all levels of the gonadotrope axis. Inactivating mutations of DAX1 result in the X-linked form of AHC with associated hypogonadotropic hypogonadism. AHC usually reveals itself as adrenal failure in early infancy, although a wide range of phenotypic expression has been reported. We describe a patient who was diagnosed with adrenal failure at 6 wk of age, but who experienced 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 putative protein encoded by this mutated gene is 429 amino acids long. The initial 389 residues probably correspond to the wild-type DAX-1 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 confirm the absence of repressor activity exerted by such mutant protein. These studies expand the genotypic and phenotypic spectrum of DAX-1 insufficiency in humans.
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PMID:Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1. 1221 54

Keratosis follicularis spinulosa decalvans (KFSD) or Siemens-1 syndrome is a rare X-linked disease of unknown etiology affecting the skin and the eye. Although most affected families are compatible with X-linked inheritance, KFSD appears to be clinically and genetically heterogeneous. So far, the gene has been mapped to Xp22.13p22.2 in two extended KFSD families. Analysis of additional recombination events in the first Dutch pedigree located the gene to an interval covering approximately 1 Mb between markers DXS7163 and DXS7593/DXS7105, whereas haplotype reconstruction in the second German family positioned the gene outside the previously identified region, proximal to marker DXS274. We report here the molecular characterization of an Xp21.1p22.12 duplication present in a patient affected with dosage-sensitive sex reversal (DSS) and KFSD. The duplicated region includes both the DAX1 gene (previously demonstrated to be responsible for DSS) and the KFSD interval, in which the gene encoding spermidine/spermine N(1)-acetyltransferase ( SSAT) is located. This enzyme catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, the spermine can be converted to spermidine and the spermidine to putrescine. Overexpression of the SSAT enzyme in a mouse model results in putrescine accumulation and a phenotype with skin and hair abnormalities reminiscent of human KFSD. Analysis of polyamine metabolism in the cells of the patient indicated that the levels of metabolites such as putrescine, spermidine and spermine were consistent with the overexpression of the SSAT gene as in the murine model. Thus, we propose that overexpression of SSAT and the consequent putrescine accumulation are involved in the KFSD phenotype, at least in our propositus.
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PMID:Gene dosage of the spermidine/spermine N(1)-acetyltransferase ( SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). 1221 35

Mutations in DAX1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NR0B1] cause X-linked AHC, a disease characterized by primary adrenal failure in infancy or childhood and reproductive abnormalities later in life. Most of these patients have nonsense or frameshift mutations that cause premature truncation of the DAX1 protein, thereby eliminating its transcriptional silencing activity. We evaluated a patient with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure. DNA sequence analysis revealed a novel amino-terminal DAX1 nonsense mutation (Q37X), predicted to cause a severe truncation of the protein. Using a combination of in vitro translation assays and studies of DAX1 expression and function in transfected cells, we demonstrate 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. Thus, this case demonstrates 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.
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PMID:An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita. 1251 85


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