title: DAX1 mutations map to putative structural domains in a deduced three-dimensional model.
abstract: The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1.
authors.affiliation: Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Guo
authors.forename: R L
authors.initials: RL
authors.lastname: Wagner
authors.forename: B L
authors.initials: BL
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: McCabe
authors.forename: E
authors.initials: E
authors.lastname: Vilain
authors.forename: T P
authors.initials: TP
authors.lastname: Burris
authors.forename: K
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: A H
authors.initials: AH
authors.lastname: Burghes
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.forename: A E
authors.initials: AE
authors.lastname: Chudley
authors.forename: M
authors.initials: M
authors.lastname: Genel
authors.forename: J M
authors.initials: JM
authors.lastname: Gertner
authors.forename: G J
authors.initials: GJ
authors.lastname: Klingensmith
authors.forename: S N
authors.initials: SN
authors.lastname: Levine
authors.forename: J
authors.initials: J
authors.lastname: Nakamoto
authors.forename: M I
authors.initials: MI
authors.lastname: New
authors.forename: R A
authors.initials: RA
authors.lastname: Pagon
authors.forename: J G
authors.initials: JG
authors.lastname: Pappas
authors.forename: C A
authors.initials: CA
authors.lastname: Quigley
authors.forename: I M
authors.initials: IM
authors.lastname: Rosenthal
authors.forename: J D
authors.initials: JD
authors.lastname: Baxter
authors.forename: R J
authors.initials: RJ
authors.lastname: Fletterick
authors.forename: E R
authors.initials: ER
authors.lastname: McCabe
mesh_terms: D000311:Adrenal Glands / Q000002:abnormalities; D000595:Amino Acid Sequence; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics*; D012097:Repressor Proteins; D017421:Sequence Analysis; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics*; 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