Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Abstract

Adrenal hypoplasia congenita (AHC) is an X-linked disorder characterized by primary adrenal insufficiency. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder but is thought not to be caused by the low adrenal androgen levels due to adrenal hypoplasia. It is uncertain whether there are two distinct yet physically linked genes responsible for AHC and HHG or a single gene responsible for both diseases. AHC can occur as a part of a contiguous deletion syndrome together with Duchenne muscular dystrophy (DMD) and/or glycerol kinase deficiency (GKD). From the analysis of deletions, the following gene order has been deduced: Xpter-AHC-GKD-DMD-cen. An AHC critical region of 200-500 kilobases has been defined by physical mapping and partially overlaps with a 160-kilobase dosage-sensitive sex (DSS) reversal critical region. The DAX-1 (DSS-AHC critical region on the X, gene 1) gene was isolated and found to encode a new member of the nuclear hormone receptor family. Here we report that DAX-1 is deleted in 14 patients and point mutations were found in the coding region in DNA from 12 unrelated individuals. All AHC patients over 14 years old and with only point mutations in DAX-1 were also diagnosed with HHG, confirming that the DAX-1 gene is responsible for both X-linked AHC and HHG. But in four sporadic cases and a single familial case, no point mutations were found, suggesting genetic heterogeneity or differential expression of DAX-1.

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

“…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-…”

“…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-family that lacks the typical zinc finger DNA-binding motif, but retains the ligand-binding domain [1].…”

“…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].…”

“…The DAX-1 protein is expressed in the adrenal cortex, gonads, anterior pituitary and hypothalamus, and DAX-1 is likely to be involved for the normal development and function of the hypothalamic-pituitarygonadal and adrenal axis [1,2]. Furthermore, studies using Ahch (the mouse Dax1 homologue) knockout mice indicated that DAX-1 also plays a direct role in spermatogenesis [14,15].…”