RESUMEN

Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer. The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown. We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1). DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T-->Arg226Stop). Thus, a homozygous germ-line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1.

Asunto(s)

Reparación del ADN , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Neurofibromatosis 1/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras , ADN/química , Femenino , Humanos , Masculino , Homólogo 1 de la Proteína MutL , Proteínas de Neoplasias/deficiencia , Proteínas Nucleares