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 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.