title: Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita.
abstract: The DAX-1 [DSS (dosage-sensitive sex)-AHC critical region in the X, gene 1] gene has been reported to be responsible for X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. However, the function and structure of the DAX-1 protein have not been characterized. In this study, molecular analysis of the DAX-1 gene from 6 patients 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, had a nonsense mutation at position 91 (Y91X). Case 4 had a 2-base deletion (AT) at nucleotides 1610 and 1611 and a 1-base insertion (G) resulting 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 messenger 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 acids, is necessary for normal adrenal cortical embryogenesis.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakae
authors.forename: T
authors.initials: T
authors.lastname: Tajima
authors.forename: S
authors.initials: S
authors.lastname: Kusuda
authors.forename: N
authors.initials: N
authors.lastname: Kohda
authors.forename: T
authors.initials: T
authors.lastname: Okabe
authors.forename: N
authors.initials: N
authors.lastname: Shinohara
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Murashita
authors.forename: T
authors.initials: T
authors.lastname: Mukai
authors.forename: K
authors.initials: K
authors.lastname: Imanaka
authors.forename: K
authors.initials: K
authors.lastname: Fujieda
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D017931:DNA Primers; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors