RESUMO
Nijmegen breakage syndrome (NBS, OMIM 251260) is a rare hereditary disease, characterized by immune deficiency, microcephaly, and an extremely high incidence of lymphoid tissue malignancies. The gene mutated in NBS, NBS1, was recently cloned from its location on chromosome 8q21. The encoded protein, nibrin (p95), together with hMre11 and hRad50, is involved in the double-strand DNA break repair system. We screened two Russian cohorts for the 657del5 NBS1 mutation and found no carriers in 548 controls and two carriers in 68 patients with lymphoid malignancies: one with acute lymphoblastic leukemia (ALL) and one with non-Hodgkin lymphoma (NHL). Several relatives of the second patient, who were carriers of the same mutation, had cancer (ALL, breast cancer, GI cancers). These preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders.
Assuntos
Quebra Cromossômica/genética , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Mutação , Deleção de Sequência , Sequência de Bases , Criança , Pré-Escolar , Cromossomos Humanos Par 8 , Estudos de Coortes , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Humanos , Perda de Heterozigosidade , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Linhagem , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Federação Russa , SíndromeRESUMO
Wiskott-Aldrich syndrome (WAS), an inherited blood cell disorder due to mutations of the X-chromosome gene WASP (Wiskott-Aldrich Syndrome Protein), was characterized originally by thrombocytopenia, immunodeficiency and eczema. Whereas platelet dysfunction is severe and consistent, immune defects are clinically variable, ranging from negligible to life-threatening. To understand this heterogeneity, WASP was quantified in peripheral blood mononuclear cells of patients with diverse mutations. In this study we assessed the relationship between the mutation, protein expression and phenotype in WAS patients. The majority of the patients with missense mutations exhibited mild phenotype, whereas patients with premature stop codon were in most cases severe. We designed a one-step approach intended for use in identifying mutations in samples from newly diagnosed patients. The approach relies on direct sequencing of amplified exon regions in a staggered schedule that was based on the mutation distribution frequency in previous cases. The method proved to be fast and reliable. Definitive mutation information was generated for each patient studied.