RESUMO
Duplications of a chromosome Xp21 locus DSS (Dosage Sensitive Sex reversal) are associated with male to female sex reversal. An unusual member of the nuclear hormone receptor superfamily, DAX1, maps to the DSS critical region and is responsible for X-linked adrenal hypoplasia congenita. Here we describe the isolation of the mouse Dax1 gene and its pattern of expression during development. Expression was detected in the first stages of gonadal and adrenal differentiation and in the developing hypothalamus. Moreover, Dax1 expression is down-regulated coincident with overt differentiation in the testis, but persists in the developing ovary. Comparison of the predicted protein products of the human and mouse genes show that specific domains are evolving rapidly. Our results suggest a basis for adrenal insufficiency and hypogonadotropic hypogonadism in males affected by adrenal hypoplasia congenita and are consistent with a role for DAX1 in gonadal sex determination.
Assuntos
Glândulas Suprarrenais/fisiologia , Proteínas de Ligação a DNA/genética , Hipotálamo/fisiologia , Receptores do Ácido Retinoico/genética , Proteínas Repressoras , Análise para Determinação do Sexo , Fatores de Transcrição/genética , Cromossomo X/genética , Glândulas Suprarrenais/anormalidades , Glândulas Suprarrenais/crescimento & desenvolvimento , Sequência de Aminoácidos , Animais , Sequência de Bases , Receptor Nuclear Órfão DAX-1 , DNA Complementar/genética , Transtornos do Desenvolvimento Sexual , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Hipogonadismo/genética , Hipotálamo/crescimento & desenvolvimento , Hibridização In Situ , Camundongos , Dados de Sequência Molecular , Família Multigênica , Homologia de Sequência do Ácido Nucleico , Especificidade da EspécieRESUMO
X-linked adrenal hypoplasia congenita is a developmental disorder of the human adrenal gland that results in profound hormonal deficiencies and is lethal if untreated. We have isolated the gene responsible for the disease, DAX-1, which is deleted or mutated in X-linked adrenal hypoplasia patients. DAX-1 encodes a new member of the nuclear hormone receptor superfamily displaying a novel DNA-binding domain. The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor.