title: A familial missense mutation in the hinge region of DAX1 associated with late-onset AHC in a prepubertal female.
abstract: Mutations in the DAX1 (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita (AHC) critical region on the X chromosome gene 1; NR0B1) cause X-linked AHC, a disease characterized by primary adrenal failure in infancy and hypogonadotropic hypogonadism. All known missense mutations impair DAX1 repression of steroidogenic factor 1 (SF1) transactivation and have been localized to the putative ligand binding domain. Here, an asymptomatic father and his late-onset AHC daughter were both shown to share a novel DAX1 mutation (C200W), the first missense mutation identified in the hinge region of DAX1. Using immunohistochemistry we demonstrate that the sub-cellular localization of the C200W mutant DAX1 protein is shifted from the nucleus to the cytoplasm. The disturbed localization of the C200W mutant in transfected cells correlates with impaired transcriptional repression activity. The import defect is relatively mild, retaining 80% of wild-type activity, which may explain the unusually mild phenotype. Import of DAX1 into the nucleus involves a direct interaction with SF1. In vitro assays demonstrate that the C200W mutant retains the ability to functionally interact with SF1, which suggests that SF1-independent interactions of DAX1 could be responsible for the import defect.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095-7088, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernard
authors.forename: Louisa
authors.initials: L
authors.lastname: Ludbrook
authors.forename: Gloria
authors.initials: G
authors.lastname: Queipo
authors.forename: Mary-Beth
authors.initials: MB
authors.lastname: Dinulos
authors.forename: Gad B
authors.initials: GB
authors.lastname: Kletter
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Zhang
authors.forename: James K
authors.initials: JK
authors.lastname: Phelan
authors.forename: Edward R B
authors.initials: ER
authors.lastname: McCabe
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
mesh_terms: D021581:Active Transport, Cell Nucleus; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D011485:Protein Binding; D021381:Protein Transport; D011627:Puberty; D000072260:RNA Splicing Factors; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C539966:Nr0b1 protein, mouse; D000072260:RNA Splicing Factors; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; C107467:SF1 protein, human; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse