Identification of a Novel Missense Mutation That Is as Damaging to DAX-1 Repressor Function as a Nonsense Mutation

• Published in: The journal of clinical endocrinology and metabolism Vol. 88; no. 3; pp. 1341 - 1349
• Main Authors: Brown, Pamela, Scobie, Graeme A., Townsend, Julie, Bayne, Rosemary A. L., Seckl, Jonathan R., Saunders, Philippa T. K., Anderson, Richard A.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.03.2003; Endocrine Society
• Subjects: Adrenal Glands - abnormalities; Adult; Biological and medical sciences; Child; Chorionic gonadotropin; Codon, Nonsense; Congenital adrenal hypoplasia; DAX-1 gene; DAX-1 Orphan Nuclear Receptor; Developmental stages; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Endocrinopathies; Gonadotropins; Humans; Hypogonadism; Hypogonadism - genetics; Hypoplasia; Hypothalamus. Hypophysis. Epiphysis (diseases); Male; Medical sciences; Missense mutation; Mutation; Mutation, Missense; Neonates; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Nonsense mutation; Pituitary (anterior); Puberty; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - physiology; Repressor Proteins - physiology; Steroidogenic Factor 1; Stop codon; Testes; Testis - pathology; Transcription Factors - genetics; Transcription Factors - physiology; Transfection; Endocrinopathy; Human; Hypoplasia; Congenital; Adrenal glands; Nonsense mutation; Genotype; Male; Gonadotropin; Congenital disease; Genetic determinism; Placental hormone; Leydig cell; Case study; Human chorionic gonadotrophin; Target tissue resistance; Phenotype; Missense mutation; Newborn; Etiology; Adrenal gland diseases; Genetics; Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2002-021560

Mutations in the DAX-1 (NROB1) gene result in X-linked congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism. The clinical presentation is usually as adrenal insufficiency in early life, with hypogonadotropic hypogonadism detected at the time of expected puberty. In this study we identified mutations in the DAX-1 gene of two patients with AHC. One mutation, Y399X, resulted in a premature stop codon and was associated with loss of Leydig cell responsiveness to human chorionic gonadotropin. The second, L297P, was a missense mutation, and human chorionic gonadotropin responsiveness was maintained. Kindred analysis established that the mutations had been inherited from the proband’s mothers. The L297P has not been described previously and occurs within a highly conserved binding motif (LLXLXL). Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity. Immunohistochemical analysis of testicular tissue obtained from an affected sibling of the subject with the Y399X mutation, who had died with adrenal failure as a neonate, showed normal testicular morphology and expression of DAX-1, steroidogenic factor-1, and anti-Mullerian hormone protein. These data extend the clinical and molecular information on DAX-1 mutations, confirm normal testicular development at the neonatal stage, and illustrate variability in Leydig cell function.