An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency
ABSTRACT Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes.
The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations.
We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1.
The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins.
We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.
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ABSTRACT: Objective: To search for mutations in DAX1/NR0B1A gene in siblings to establish the molecular etiology of the adrenal hypoplasia congenita (AHC), a rare potentially life-threatening disorder. Case report: We describe two siblings who presented with salt-wasting syndrome in the new- born period and received hormonal replacement for primary adrenal insufficiency. A diagnostic hypothesis of AHC was suspected because the children maintained, during hormonal treatment, low plasma 17-OH progesterone (17-OHP) and androgens, despite high ACTH levels. Results: DAX1 gene was studied by molecular analysis, which showed a mutation, confirming the diag- nosis in the siblings and a heterozygous state in the mother. Direct sequencing of DAX1 revealed an insertion of an adenine base (c1382-1383 A ins), which lead to a pMet461Asp substitution. Conclusion: A novel frameshift mutation of DAX1 gene, which established the molecular etiolo- gy of the AHC in the siblings, was identified. Obtaining a precise genetic diagnosis of this adrenal disorder, which, sometimes, cannot be confirmed only by clinical aspects, may have important implications for the long-term management of the disease. Arq Bras Endocrinol Metab. 2009;53(6):771-6
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ABSTRACT: Abstract We report the case of a 12-year-old boy with a de novo mutation in the DAX1 gene (for dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1; also called NROB1). He was born at term, Addison's disease was diagnosed at 8 years with a salt-wasting syndrome, and then hydrocortisone substitution was taken; the child continued to develop normally. A reoccurrence of salt-wasting syndrome usually happened after an episode of an abrupt withdrawal of hydrocortisone substitution. Because of adrenal insufficiency without hypogonadotropic hypogonadism, he came to the clinic at 12 years of age and hypoplasia of adrenal glands was found by MRI scans. We proposed the diagnosis of congenital adrenal hypoplasia in this patient and identified a hemizygous mutation (c.999_1000insCTCA, p.Leu335ThrfsX389) in exon 1 of the DAX1 gene. To our knowledge, it is a de novo mutation that leads to a frame-shift, a premature stop codon. In conclusion, it is very important to identify mutation in the DAX1 gene for a boy with adrenal insufficiency of unknown etiology.Journal of pediatric endocrinology & metabolism: JPEM 11/2013; 27(3-4):1-5. DOI:10.1515/jpem-2013-0260 · 0.71 Impact Factor
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ABSTRACT: Abstract Patients with DAX-1gene mutations on chromosome Xp21 usually present with adrenal hypoplasia congenita and hypo\xadgonadotropic hypogonadism. Yet, neither correlation between the type of mutation and the age of onset of the disease nor mechanism of the mutation on puberty is fully understood. Here, we report a novel non-sense p.Gln208X mutation in the amino terminal domain of the DAX-1gene observed in a large family with three boys presenting with adrenal manifestations at different ages. Furthermore, two boys developed spontaneous puberty that failed to progress at similar ages, whereas the other boy developed precocious puberty at 10 month of age. The unique structure of the DAX-1gene may explain this phenotypic variability. However, more studies are needed to understand the role of the DAX-1gene on development of the adrenal gland and hypothalamus-pituitary-gonadal axis.Journal of pediatric endocrinology & metabolism: JPEM 06/2012; 26(5-6):1-5. DOI:10.1515/jpem-2012-0086 · 0.71 Impact Factor