RESUMO
Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.
Assuntos
Proteínas de Ligação a DNA , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas , Trombocitopenia/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Sequência de Bases , Plaquetas/metabolismo , Mapeamento Cromossômico , Ensaio de Unidades Formadoras de Colônias , Subunidade alfa 2 de Fator de Ligação ao Core , Análise Mutacional de DNA , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Hematopoese/genética , Heterozigoto , Humanos , Hibridização in Situ Fluorescente , Masculino , Megacariócitos/citologia , Megacariócitos/metabolismo , Repetições de Microssatélites , Dados de Sequência Molecular , Mutação , Linhagem , RNA/genética , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido NucleicoRESUMO
Egg hatch of Meloidogyne exigua was significantly inhibited in 14 days pretreatment with aldicarb, ethoprop, or carbofnran at concentrations higher than 0.1 mug/ml; these eggs were found to delay hatch in 19 days posttreatment in ethoprop. Aldicarb and carbofuran solutions at concentrations greater than 0.1 mug/ml significantly decreased the motility and the life span of the second-stage juveniles; aldicarb was more toxic than carbofuran to the nematode. In a field test, aldicarb (Temik 10G), ethoprop (Mocap 10G), and carbofuran (Furadan 5G and Furadan Liquid 350F) significantly decreased M. exigua populations.