Steroid 21-Hydroxylase Deficiency in Mice. An Animal Model for Congenital Adrenal Hyperplasia.

Abstract

The classical form of congenital adrenal hyperplasia (CAH) in humans is caused by a deficiency in steroid 21-hydroxylase (21-OHase) . The enzyme 21-OHase plays a key role in adrenal steroidogenesis. Duplicated genes for the enzyme are located in the class III region of the major histocompatibility complex (MHC), HLA. In the mouse, the genes encoding 21-OHase have been mapped to the homologous region of the H-2 complex. We have previously obtained an intra-H-2 recombinant haplotype aw18 from a cross between H-2 congenic strains of B10. A (H-2a) and B10. MOL-SGR (H-2wm7), which carries the H-2 complex derived from the Japanese wild mouse. When mice that were heterozygous for aw18 were intercrossed, no mice that were homozygous for the aw18 haplotype were detected among live offspring of more than 15 days of age, which suggested presence of a recessive lethal gene in the H-2aw18 haplotype. Molecular analysis of the H-2aw18 chromosome has revealed a deletion in the H-2 class III region encompassing the gene for the complement component C4 and one of two genes for 21-OHase. We now report that newborn aw18 homozygous mice are deficient in 21-OHase activity, and that homozygosity of the aw18 haplotype directly causes death at the early postnatal stage. Morphological changes in the adrenal glands of newborn aw18 homozygotes are also observed. The aw18 recombinant haplotype is expected to serve as a useful animal model for the inherited human disease of CAH.