Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita

• Published in: The journal of clinical endocrinology and metabolism Vol. 81; no. 10; pp. 3680 - 3685
• Main Authors: NAKAE, J, TAJIMA, T, FUJIEDA, K, KUSUDA, S, KOHDA, N, OKABE, T, SHINOHARA, N, KATO, M, MURASHITA, M, MUKAI, T, IMANAKA, K
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01-10-1996
• Subjects: Adolescent; Adrenal Insufficiency - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Child, Preschool; DAX-1 Orphan Nuclear Receptor; DNA Mutational Analysis; DNA Primers; DNA-Binding Proteins - genetics; Endocrinopathies; Gene Deletion; Genetic Linkage; Humans; Infant; Male; Medical sciences; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Polymerase Chain Reaction; Receptors, Retinoic Acid - genetics; Repressor Proteins; RNA, Messenger - analysis; Sequence Analysis, DNA; Transcription Factors - genetics; X Chromosome; Endocrinopathy; Human; Hypoplasia; Polymerase chain reaction; Genetic inheritance; Adrenal insufficiency; Adrenal glands; Pathogenesis; Adrenal gland diseases; Mutation; Molecular biology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.81.10.3680

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.