title: Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita.
abstract: The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291 Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakae
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Tajima
authors.forename: N
authors.initials: N
authors.lastname: Shinohara
authors.forename: M
authors.initials: M
authors.lastname: Murashita
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.forename: S
authors.initials: S
authors.lastname: Kusuda
authors.forename: J
authors.initials: J
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Fujieda
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016368:Frameshift Mutation; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; 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