MUTATIONS IN THE DAX-1 GENE GIVE RISE TO BOTH X-LINKED ADRENAL HYPOPLASIA CONGENITA AND HYPOGONADOTROPIC HYPOGONADISM

ADRENAL hypoplasia congenita (AHC) is an X-linked disorder characteriz ed by primary adrenal insufficiency(1,2). Hypogonadotropic hypogonadis m (HHG) is frequently associated with this disorder but is thought not to be caused by the low adrenal androgen levels due to adrenal hypopl asia(3,4). It is uncertain whether there are two distinct yet physical ly linked genes responsible for AHC and HHG or a single gene responsib le for both diseases. AHC can occur as a part of a contiguous deletion syndrome together with Duchenne muscular dystrophy (DMD) and/or glyce rol kinase deficiency (GKD). From the analysis of deletions, the follo wing gene order has been deduced: Xpter-AHC-GKD-DMD-cen(5,6). An AHC c ritical region of 200-500 kilobases has been defined by physical mappi ng(7,8) and partially overlaps with a 160-kilobase dosage-sensitive se x (DSS) reversal critical region(9). The DAX-1 (DSS-AHC critical regio n on the X, gene 1) gene was isolated and found to encode a new member of the nuclear hormone receptor family(10). Here we report that DAX-1 is deleted in 14 patients and point mutations were found in the codin g region in DNA from 12 unrelated individuals. All AHC patients over 1 4 years old and with only point mutations in DAX-1 mere also diagnosed with HHG, confirming that the DAX-1 gene is responsible for both X-li nked AHC and HHG. But in four sporadic cases and a single familial cas e, no point mutations were found, suggesting genetic heterogeneity or differential expression of DAX-1.