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

Abstract

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...

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

“…[6,8,10,12,16]. However, Tabarin et al [3]. described a patient with late onset adrenal insufficiency and incomplete HHG allowing partial pubertal development and significant masculinization.…”

“…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 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].…”

“…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].…”

Clinical and molecular analysis of human reproductive disorders in Brazilian patients

“…Mutations in this gene in humans cause an X-linked adrenal cytomegalic form of adrenal hypoplasia and HH (17,18). Recently, a unique case extended the clinical spectrum of the disease including mild forms of HH, delayed-onset of adrenal insufficiency and abnormal spermatogenesis (19). The majority of DAX1 mutations reported are frameshift or nonsense mutations.…”