F. Muscatelli et al., MUTATIONS IN THE DAX-1 GENE GIVE RISE TO BOTH X-LINKED ADRENAL HYPOPLASIA CONGENITA AND HYPOGONADOTROPIC HYPOGONADISM, Nature, 372(6507), 1994, pp. 672-676
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.