A TRANSCRIPTIONAL SILENCING DOMAIN IN DAX-1 WHOSE MUTATION CAUSES ADRENAL HYPOPLASIA CONGENITA

The DAX-1 gene encodes an unusual member of the nuclear hormone recept or superfamily. Mutations in the human DAX-1 gene cause X-linked adren al hypoplasia congenita associated with hypogonadotropic hypogonadism. We have shown that DAX-1 binds to hairpin secondary structures and bl ocks steroidogenesis in adrenal cells via transcriptional repression o f the steroidogenic acute regulatory protein (StAR) promoter. Here we have investigated the molecular mechanism of DAX-1-mediated repression . We show that the DAX-1 C terminus contains a potent transcriptional silencing activity, which can be transferred to a heterologous DNA-bin ding domain. Deletion analysis and modeling of DAX-1 structure identif y two cooperating domains required for the silencing function, one loc ated within helix H3 and the other within H12. The silencing function is cell- and promoter-specific. Strikingly, two point mutations (R267P and Delta V269) found in adrenal hypoplasia patients impair silencing . These findings suggest that transcriptional silencing by DAX-1 plays a critical role in the pathogenesis of adrenal hypoplasia congenita.