title: Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression.
abstract: DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamic-pituitary gonadal axis. Mutations in the gene encoding DAX-1 result in X-linked adrenal hypoplasia congenita (AHC). Affected boys typically present with primary adrenal failure in infancy or childhood and hypogonadotropic hypogonadism at the time of puberty. The majority of DAX1 mutations described to date are nonsense or frameshift mutations that result in premature truncation of the DAX-1 protein and loss of DAX-1 repressor function. Relatively few missense mutations in DAX1 have been reported. Here, we describe missense mutations in three additional families with X-linked AHC. When combined with previous reports, the DAX1 missense mutations appear to cluster within restricted regions of the putative ligand-binding domain of DAX-1 and affect amino acids that are evolutionarily conserved, suggesting that these regions correspond to critical functional domains. Transcription assays, using a variety of artificial and native target genes, were performed to assess the effects of these mutations on the function of DAX-1. All DAX-1 missense mutant constructs showed marked loss of repressor function, with the exception of I439S, a mutation previously shown to be associated with delayed-onset adrenal failure and incomplete hypogonadotropic hypogonadism. These data indicate that most DAX1 missense mutations associated with classic AHC exhibit marked loss of function. The locations of these mutations thereby identify important functional domains in the carboxyl-terminus of the protein.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Achermann
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: B L
authors.initials: BL
authors.lastname: Silverman
authors.forename: R L
authors.initials: RL
authors.lastname: Habiby
authors.forename: S
authors.initials: S
authors.lastname: Pang
authors.forename: A
authors.initials: A
authors.lastname: Rosler
authors.forename: J L
authors.initials: JL
authors.lastname: Jameson
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000309:Adrenal Insufficiency / Q000235:genetics*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000450:Aldosterone / Q000097:blood; D002460:Cell Line; D003350:Cortodoxone / Q000097:blood; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004622:Embryo, Mammalian; D008040:Genetic Linkage; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006947:Hyperkalemia / Q000235:genetics; D007010:Hyponatremia / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney; D008297:Male; D020125:Mutation, Missense; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012083:Renin / Q000097:blood; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014960:X Chromosome
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D000450:Aldosterone; D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D012083:Renin; D003350:Cortodoxone; D006854:Hydrocortisone