RESUMO
Frasier syndrome is a relatively rare disorder associated with XY gonadal dysgenesis, gonadoblastoma, and kidney failure. In this report, we identify a classic mutation in the Wilms' tumor 1 gene in one of the original cases of Frasier syndrome reported in this Journal in 1964.
Assuntos
Síndrome de Denys-Drash/genética , Genes do Tumor de Wilms , Disgenesia Gonadal 46 XY/genética , Mutação Puntual , Adenina , Análise Mutacional de DNA , Feminino , Guanina , Humanos , Íntrons , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseAssuntos
Nanismo/tratamento farmacológico , Nanismo/psicologia , Hormônio do Crescimento Humano/uso terapêutico , Pais/psicologia , Adolescente , Estatura/efeitos dos fármacos , Terapia Combinada , Aconselhamento , Nanismo/genética , Humanos , Masculino , Equipe de Assistência ao Paciente , Papel do Médico , Proteínas Recombinantes/uso terapêutico , Encaminhamento e Consulta , Autoimagem , Ajustamento SocialAssuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Testosterona/uso terapêutico , Adolescente , Androgênios/administração & dosagem , Androgênios/uso terapêutico , Estatura/efeitos dos fármacos , Humanos , Masculino , Testosterona/administração & dosagemRESUMO
In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.
