TRUNCATION AT THE C-TERMINUS OF THE DAX-1 PROTEIN IMPAIRS ITS BIOLOGICAL ACTIONS IN PATIENTS WITH X-LINKED ADRENAL HYPOPLASIA CONGENITA

The DAX-1 [DSS (dosage-sensitive sex)-AHC critical region in the X, ge ne 1] gene has been reported to be responsible for X-linked adrenal hy poplasia congenita (AHC) and hypogonadotropic hypogonadism. However, t he function and structure of the DAX-1 protein have not been character ized. In this study, molecular analysis of the DAX-1 gene from 6 patie nts with AHC, including 2 siblings, identified 5 novel mutations with 3 nonsense mutations and 2 frameshift mutations. Case 1 had a nonsense mutation at position 395 (Q395X). Cases 2 and 3, who were siblings, h ad a nonsense mutation at position 91 (Y91X). Case 4 had a 2-base dele tion (AT) at nucleotides 1610 and 1611 and a 1-base insertion (G) resu lting in a premature stop codon at position 462 (1610-1611 del AT ins G). Case 5 had a nonsense mutation at position 271 (Y271X). Case 6 had a 1-base deletion (C) at nucleotide 1169, which induced a frame shift and a premature stop codon at position 371 (1169 del C). All mutated DAX-1 proteins had truncated C-terminal domains. In addition, reverse transcription-PCR and direct sequencing characterized the mutant messe nger ribonucleic acid in testis from case 1. Our results suggest that these 5 novel mutations are responsible for X-linked AHC and that the C-terminus of the DAX-1 protein, especially the terminal 11 amino acid s, is necessary for normal adrenal cortical embryogenesis.