title: New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.
abstract: Congenital adrenal hypoplasia, an X-linked disorder, is characterized by primary adrenal insufficiency and frequent association with hypogonadotropic hypogonadism. The X-chromosome gene DAX-1 has been most recently identified and shown to be responsible for this disorder. We analyzed the DAX-1 genes of two unrelated Japanese patients with congenital adrenal hypoplasia and hypogonadotropic hypogonadism by using PCR amplification of genomic DNA and its complete exonic sequencing. In a family containing several affected individuals, the proband male patient had a stop codon (TGA) in place of tryptophan (TGG) at amino acid position 171. As expected, his mother was a heterozygous carrier for the mutation, whereas his father and unaffected brother did not carry this mutation. In another male patient with noncontributory family history, sequencing revealed a 1-bp (T) deletion at amino acid position 280, leading to a frame shift and, subsequently a premature stop codon at amino acid position 371. The presence of this mutation in the patients' genome was further confirmed by digestion of genomic PCR product with MspI created by this mutation. Family studies using MspI digestion of genomic PCR products revealed that neither parent of this individual carried the mutation. These results clearly indicate that congenital adrenal hypoplasia and hypogonadotropic hypogonadism result from not only inherited but also de novo mutation in the DAX-1 gene.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yanase
authors.forename: R
authors.initials: R
authors.lastname: Takayanagi
authors.forename: K
authors.initials: K
authors.lastname: Oba
authors.forename: Y
authors.initials: Y
authors.lastname: Nishi
authors.forename: K
authors.initials: K
authors.lastname: Ohe
authors.forename: H
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics*; D001483:Base Sequence; D003062:Codon; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D008040:Genetic Linkage; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014364:Tryptophan / Q000235:genetics; D014960:X Chromosome
chemical_list: D003062:Codon; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D014364:Tryptophan