An Amino-Terminal DAX1 ( NROB1 ) Missense Mutation Associated with Isolated Mineralocorticoid Deficiency

Utrecht University, Utrecht, Utrecht, Netherlands
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 04/2007; 92(3):755-61. DOI: 10.1210/jc.2005-2429
Source: PubMed


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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    • "Frame shift mutations affect protein function severely. These types of mutations frequently cause disease.Since the initial identification of DAX1 as the gene responsible for AHC, numerous additional mutations have been discovered including deletions, alterations of splice-sites, missense mutations, nonsense mutations and frame shift mutations (4,7,11,15,16,17,18,19,20,21,22,23,24,25,26,27). "
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    ABSTRACT: Adrenal hypoplasia congenita (AHC) is a rare disorder. The X-linked form is related to mutations in the DAX1 (NROB1) gene. Here, we report a newborn who had a novel hemizygous frameshift mutation in DAX1 (c.543delA) and presented with primary adrenal failure that was initially misdiagnosed as congenital adrenal hyperplasia. This report highlights the value of genetic testing for definite diagnosis in children with primary adrenal failure due to abnormal adrenal gland development, providing the possibility both for presymptomatic, and in cases with a sibling with this condition, for prenatal diagnosis. Conflict of interest:None declared.
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    • "In laboratory tests, hyponatremia, hyperkalemia, low levels of cortisol, aldosterone, and adrenal androgens are found, in contrast to high levels of adrenocorticotropic hormone (ACTH) and plasma renin activity (Achermann et al. 2000; Nakae et al. 1997; Wiltshire et al. 2001; Verrijn Stuart et al. 2007). Very frequently, patients are admitted to hospital in a life-threatening condition. "

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    • "SF1 stimulates the DAX1 promoter (Yu, Ito and Jameson, 1998). Although DAX1 typically represses SF1-mediated transcription, low doses of DAX1 can activate certain SF1-regulated promoters, such as CYP11A1 and CYP11B1 (Verrijn Stuart et al., 2007). Perhaps more important from a physiologic perspective, both SF1 and DAX1 play important, and incompletely understood, roles in development. "
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    ABSTRACT: DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies.
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