&lt;i&gt;DAX&lt;/i&gt;&lt;i&gt;-&lt;/i&gt;1 Gene Mutations and Deletions in Japanese Patients with Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism

Kinoshita, Ei Ichi; Yoshimoto, Masaaki; Motomura, Katsuaki; Kawaguchi, Tomonori; Mori, Ryogo; Baba, Toru; Nishijo, Kahoru; Hasegawa, Tomonobu; Momoi, T; Yorihuji, Tom

doi:10.1159/000185364

Cited by 22 publications

(14 citation statements)

References 12 publications

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“…Remarkably, all mutations associated with AHC reported to date alter the structure of the carboxy terminus of the DAX-1 protein (1,11,13,26,27,29,32,33,35,(48)(49)(50)(51)(52)(53)(54)(55)(56). The majority of these are frameshift or nonsense (stop codon) mutations that result in a truncated protein.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Tabarin¹,

Achermann²,

Récan³

et al. 2000

J. Clin. Invest.

177

131

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IntroductionThe DAX1 gene encodes an orphan member of the nuclear receptor superfamily that lacks the typical zinc finger DNA-binding motif, but retains the ligand-binding domain characteristic of other family members (1). DAX-1 is expressed in the adrenal cortex, gonads, hypothalamus and anterior pituitary (2). It interacts with another orphan nuclear receptor, steroidogenic factor-1 (SF-1) (3), which plays a pivotal role in the development and function of these tissues (4-9). In vitro studies suggest that DAX-1 represses SF-1-mediated transcription, but the roles of SF-1 and DAX-1 in the development and function of these tissues remain unclear (5-7). Recent results obtained in Ahch (the mouse Dax1 homologue) knockout mice suggest that DAX-1 may also play a direct role in spermatogenesis (10).Mutations in the DAX1 gene in humans cause the Xlinked cytomegalic form of adrenal hypoplasia congenita (AHC), a rare disorder characterized by impaired development of the permanent zone of the adrenal cortex and hypogonadotropic hypogonadism (HHG) (1, 11). Affected boys develop adrenal failure shortly after birth or during early childhood, whereas HHG, a universal feature of the syndrome, is usually recognized at the expected time of puberty (9, 12, 13). Whether or not DAX1 mutations affect spermatogenesis in humans, independent of the effects of gonadotropin deficiency, remains unknown (9).In this report, we describe the clinical features of a patient with a mild phenotypic presentation of AHC and examine the functional properties of the mutant DAX-1 protein. In addition, we describe the results of exogenous gonadotropin therapy on spermatogenesis. Recognition of this unique phenotype is of practical importance because it extends the clinical spectrum of the disease to include mild forms of HHG and delayed onset of adrenal insufficiency. Studies in this patient also suggest that DAX-1 function is required for spermatogenesis in humans, independent of gonadotropin and testosterone production. Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). In affected boys, primary adrenal insufficiency occurs soon after birth or during early childhood; HHG is recognized at the expected time of puberty. In this report, we describe the novel phenotype of a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development and undiagnosed incomplete HHG. Gonadotropin therapy did not improve his marked oligospermia, suggesting a concomitant primary testicular abnormality. Genomic analysis revealed a novel missense mutation, I439S, in DAX1. The mutant DAX-1 protein was studied 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 DAX-1 when compared with mutations associated with classic AHC. This unique case extends the clinical spectrum of AHC to include de...

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Section: Discussionmentioning

confidence: 99%

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Tabarin¹,

Achermann²,

Récan³

et al. 2000

J. Clin. Invest.

177

131

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“…The DAX-1 gene encodes an orphan member of the nuclear hormone receptor super-family that lacks the typical zinc finger DNA-binding motif, but retains the ligand-binding domain [1]. To date gene deletions and more than 70 different mutations of the DAX-1 gene including frame shift mutations, nonsense and missense mutations have been identified in human with X-linked AHC [1,[4][5][6][7][8][9][10][11][12][13].…”

mentioning

confidence: 99%

Four Japanese Patients with Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism Caused by DAX-1 Gene Mutations: Mutant DAX-1 Failed to Repress Steroidogenic Acute Regulatory Protein (StAR) and Luteinizing Hormone .BETA.-subunit Gene Promoter Activity

Okuhara

Abe

Kondo³

et al. 2008

Endocr J

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Abstract. Mutations of DSS (dosage sensitive sex reversal)-AHC critical region on the X chromosome, gene 1 DAX-1(NROB1)] results in X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Here we report four Japanese patients with AHC and HHG caused by the mutations of the DAX-1 gene. All patients manifested adrenal crisis at early childhood. Three patients did not show any pubertal sign and were diagnosed as having HHG. One patient manifested spontaneous pubertal development at 17 years of age. Nevertheless, his puberty did not develop further and his gonadotropin and testosterone levels decreased thereafter. Therefore, he was also diagnosed as having HHG. We performed testicular biopsy in another patient with HHG. Histological examination demonstrated Sertoli cell hypoplasia and no sperm formation in the seminiferous tubules. Molecular analysis demonstrated two novel point mutations (V269D and L278R) in two patients. Transient transfection assays showed that all these mutations (V269D, L271X, L278R, and Q395X) abolished the repression activity to both StAR and LHβ gene promoter activation. In conclusion, we reported patients with AHC and HHG caused by the loss of function mutations of the DAX-1 gene. X-LINKED adrenal hypoplasia congenita (AHC) is a congenital disorder characterized by adrenal insufficiency and hypogonadotropic hypogonadism (HHG). Salt-losing adrenal insufficiency usually occurs during the neonatal period or during childhood [1,2], although one patient with adult onset of adrenal insufficiency has been described [3]. HHG caused by DAX-1 mutation is diagnosed by the absence of pubertal development. HHG is thought to be caused by disturbances at both the hypothalamic and pituitary levels; however, the exact mechanism of HHG is still unknown [3][4][5]. Dosage-sensitive sex reversal-AHC critical region on the X chromosome, gene 1 (DAX-1) was cloned and this gene was found to be responsible for X-linked AHC and HHG [1]. The DAX-1 gene encodes an orphan member of the nuclear hormone receptor super-

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“…1 All patients described to date have been male, and female carriers have had no clinical symptoms. [1][2][3][4][5][6][7][8][9][10] Although most patients present with adrenal crisis in the neonatal period, the onset of adrenal insufficiency varies, even within a family, from the neonatal period to 10 years of age. 1,3,4,9 The gene responsible for this disorder, DAX1, is on the short arm of the X chromosome 11 and encodes a 470-amino-acid member of the nuclear hormone receptor superfamily.…”

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confidence: 99%

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

et al. 1999

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<i>DAX</i><i>-</i>1 Gene Mutations and Deletions in Japanese Patients with Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism

Cited by 22 publications

References 12 publications

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism

Four Japanese Patients with Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism Caused by DAX-1 Gene Mutations: Mutant DAX-1 Failed to Repress Steroidogenic Acute Regulatory Protein (StAR) and Luteinizing Hormone .BETA.-subunit Gene Promoter Activity

Hypogonadotropic Hypogonadism in a Female Caused by an X-Linked Recessive Mutation in theDAX1Gene

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