RESUMO
Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression.
Assuntos
DNA Helicases/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Talassemia alfa/genética , Sequência de Bases , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , DNA/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Globinas/genética , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Proteína Nuclear Ligada ao XRESUMO
ATRX belongs to the SNF2 family of proteins, many of which have been demonstrated to have chromatin remodeling activity. Constitution mutations in the X-encoded gene give rise to alpha thalassemia mental retardation (ATR-X) syndrome and a variety of related conditions that are often associated with profound developmental delay, facial dysmorphism, genital abnormalities, and alpha thalassemia. Acquired mutations in ATRX are observed in the preleukemic condition alpha thalassemia myelodysplastic syndrome (ATMDS). Mutations in ATRX have been shown to perturb gene expression and DNA methylation. This is a comprehensive report of 127 mutations including 32 reported here for the first time. Missense mutations are shown to cluster in the two main functional domains. The truncating mutations appear to be "rescued" to some degree and so it appears likely that most if not all constitutional ATRX mutations are hypomorphs.