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Case Reports
. 2000 Feb;105(3):321-8.
doi: 10.1172/JCI7212.

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

A Tabarin  1 , J C Achermann, D Recan, V Bex, X Bertagna, S Christin-Maitre, M Ito, J L Jameson, P Bouchard
Affiliations
Case Reports

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

A Tabarin et al. J Clin Invest. 2000 Feb.

Abstract

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 delayed-onset primary adrenal insufficiency in adulthood and milder forms of HHG. Furthermore, in accordance with findings in Ahch (Dax1) knockout mice, the clinical features in this patient suggest that DAX-1 function is required for spermatogenesis in humans, independent of its known effects on gonadotropin production.

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Figures

Figure 1
Figure 1
Endogenous LH (filled circles) and FAS (open triangles) determination at 10-minute intervals for 6 hours. Asterisks and underlined asterisks denote FAS and LH pulses, respectively.
Figure 2
Figure 2
Response of the gonadotropic axis to GnRH analogue injection. (a) Serum FSH (open circles), LH (filled circles), and FAS (closed triangles) concentrations measured at 4-hour intervals for 24 hours after injection of the GnRH analogue agonist triptorelin. (b) Serum testosterone measured at 4-hour intervals for 24 hours after injection of the GnRH analogue agonist triptorelin. Note the logarithmic scale. The shaded area indicates the normal range of testosterone values in adult men.
Figure 3
Figure 3
Identification of the DAX1 missense mutation. (a) Chromatogram showing the I439S missense mutation in exon 2 of DAX1. A guanine is present at nucleotide position 1316 in the patient (arrow), whereas a thymine is present at the equivalent position in a genomic sequence from a control subject. (b) The thymine-to-guanine nucleotide change creates a novel BsrDI site. PCR products from the patient, his mother, his normal brother, his father, and a normal control were digested with this restriction enzyme (lanes 1–5, respectively). The mutated fragment, characterized by a band 13 bp shorter than the wild-type fragment, is present in the patient and his mother (arrows).
Figure 4
Figure 4
Functional effects of the I439S DAX-1 mutant. (a) Schematic representation of the DAX-1 mutant constructs studied. (b) The effect of wild-type DAX-1 and its mutants on basal transcriptional activity was studied using 25 ng of a pBIND vector containing the putative LBD (207–470) of DAX-1 fused to the GAL4 DBD, and 500 ng of a UAS-TK109luc reporter. Transient transfection studies were performed in triplicate using human tsa201 embryonic kidney cells. The mean of each triplicate reaction was expressed as a percentage of the empty vector (–) control for that study. The results represent the mean ± SEM from at least 6 independent triplicate experiments. (c) The effect of DAX-1 and its mutants on SF-1–mediated transactivation. Transfections were performed as above, using 25 ng of a pBINDGAL4 fusion protein containing the activation domain of SF-1 (FTZF1) (residues 133–461), 50 ng pCMX–DAX1 expression vector containing the full-length wild-type or mutant cDNA, and 500 ng of a UAS-TK109luc reporter. WT, wild type.
Figure 5
Figure 5
The effect of DAX-1 and its mutants on SF-1/Egr-1 synergistic activation of the rat LHβ gene promoter. Cotransfection of human SF1 (FTZF1) (20 ng) with rat Egr1 (20 ng) produced synergistic activation of the rat LHβ gene promoter (–154 to +5) (500 ng). Repression by wild-type (WT) DAX-1 (50 ng) was reduced when the R267P, ΔV269, and Δ448–470 DAX-1 mutant vectors were investigated. The I439S mutant had intermediate function.
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