Targeted disruption of StAR provides novel insights into congenital adrenal hyperplasia

To explore the function of StAR in a system that can be experimentally mani pulated, and to develop a mouse model for the human disorder lipoid congeni tal adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to p roduce a mouse line deficient in StAR protein. Initially, StAR knockout mic e were indistinguishable from wildtype littermates, except that all had fem ale external genitalia. After birth, they showed signs of either respirator y distress or volume depletion and eventually died. Hormone assays confirme d severe defects in adrenal steroids, whereas hormones constituting the gon adal axis did not differ significantly from levels in wildtype littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, as visualized with oil red O stain. Lesser lipid deposits w ere observed in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement provide evidenc e for a two-stage model of the pathogenesis of StAR deficiency, with trophi c hormone stimulation causing progressive accumulation of lipids within the steroidogenic cells which ultimately kills them. These StAR knockout mice provide a novel system in which to study StAR's essential roles in adrenoco rtical and gonadal steroidogenesis.