Clinical and functional effects of mutations in the DAX-1 gene in patientswith adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is an X-linked disorder caused by mutati ons in a gene referred to as DAX-1. AHC is characterized by adrenal insuffi ciency and failure to undergo puberty because of hypogonadotropic hypogonad ism. The DAX-1 protein is structurally related to orphan nuclear receptors, although it lacks the characteristic zinc finger DNA-binding domain that i s highly conserved in other members of this family. In this report, we desc ribe the clinical features and genetic alterations in six families with AHC . These patients reveal the variable clinical presentation of adrenal insuf ficiency in AHC and underscore the importance of considering this diagnosis . Nonsense mutations that introduce a stop codon were found in three cases (W171X, W171X, Y399X). Frameshift mutations (405delT, 501delA, and 702delC) , each of which resulted in a premature stop codon at amino acid 263, were found in the other three families. Three of these mutations (Y399X, 405delT , 702delC) are novel. Using transient gene expression assays to assess DAX- 1 function, these mutations were shown to eliminate the ability of DAX-1 to repress the transcription of genes that are stimulated by a related nuclea r receptor, steroidogenic factor-1. These studies reveal the variable clini cal presentation of DAX-1 mutations and emphasize the value genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC.