Assuntos
DNA Helicases , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Mutação , Proteínas Nucleares , Fatores de Transcrição/química , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sequência Conservada , Globinas/genética , Humanos , Deficiência Intelectual/genética , Camundongos , Dados de Sequência Molecular , Fenótipo , Homologia de Sequência de Aminoácidos , Síndrome , Proteína Nuclear Ligada ao X , Dedos de Zinco/genética , Talassemia alfa/genéticaRESUMO
We have identified two females who are mosaic for an ATRX mutation. One case, in whom the mutation was undetectable in peripheral blood and buccal cells, has two affected sons and is therefore presumed to be a germline mosaic. In another case, the ATRX mutation is weakly detectable in the peripheral blood but only one of her three children who share the disease-associated haplotype carries the mutation and therefore it is concluded that she is a gonosomal mosaic. These cases provide the first molecular evidence for the occurrence of post-zygotic mutation in X-linked alpha thalassaemia mental retardation syndrome. The possibility of germline mosaicism must therefore be considered in the genetic counselling of ATR-X families.
Assuntos
Ligação Genética , Mutação em Linhagem Germinativa , Deficiência Intelectual/genética , Mosaicismo , Cromossomo X , Talassemia alfa/genética , Metilação de DNA , Mecanismo Genético de Compensação de Dose , Feminino , Frequência do Gene , Haplótipos , Humanos , Recém-Nascido , Masculino , LinhagemRESUMO
It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.