RESUMEN
MRE11 and NBS1 function together as components of a MRE11/RAD50/NBS1 protein complex, however deficiency of either protein does not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE11A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. Here we describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) and mutations in the MRE11A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein. Their levels of radiation-induced activation of ATM were higher than those in ATLD cells.
Asunto(s)
Proteínas de Unión al ADN/genética , Microcefalia/genética , Microcefalia/patología , Mutación , Síndrome de Nijmegen/patología , Adolescente , Adulto , Apraxias/enzimología , Apraxias/metabolismo , Ataxia Telangiectasia/enzimología , Ataxia Telangiectasia/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Caspasa 3/metabolismo , Proteínas de Ciclo Celular/metabolismo , División Celular/genética , Ataxia Cerebelosa/congénito , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Activación Enzimática/genética , Femenino , Fase G2/genética , Humanos , Hipoalbuminemia/enzimología , Hipoalbuminemia/metabolismo , Lactante , Proteína Homóloga de MRE11 , Masculino , Microcefalia/metabolismo , Embarazo , Proteínas Serina-Treonina Quinasas/metabolismo , Tolerancia a Radiación/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency. We measured muscle CoQ10 levels in six patients with AOA1 and found decreased levels in five. Patients homozygous for the W279X mutation had lower values (p = 0.003). A therapeutic trial of CoQ10 may be warranted in patients with AOA1.
