RESUMEN
We report on a patient with the typical clinical findings of Emery-Dreifuss muscular dystrophy due to a mutation in the emerin gene that should have produced a higher molecular weight protein. Immunohistochemical analysis showed emerin localized only in the cytoplasm of muscle fibres and lymphoblastoid cells. The emerin molecule contained the nucleoplasmic domain and the transmembrane domain responsible for nuclear membrane targeting, so its incorrect localization and lack of function could be due to abnormal folding resulting in rapid degradation or inability to bind other nuclear proteins.
Asunto(s)
Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Emery-Dreifuss/genética , Timopoyetinas/genética , Timopoyetinas/metabolismo , Adolescente , Citoplasma/metabolismo , Citoplasma/ultraestructura , Análisis Mutacional de ADN , Humanos , Linfocitos/metabolismo , Masculino , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestructura , Proteínas Nucleares , Estructura Terciaria de Proteína/genéticaRESUMEN
Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.
Asunto(s)
Laminina/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos/genética , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Femenino , Genes Dominantes/genética , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Humanos , Lactante , Laminina/química , Laminina/metabolismo , Masculino , Persona de Mediana Edad , Distrofia Muscular de Emery-Dreifuss/metabolismo , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Linaje , Penetrancia , Polimorfismo Conformacional Retorcido-Simple , Estructura Terciaria de ProteínaRESUMEN
We have raised an anti-emerin polyclonal antibody against a fusion protein encompassing most of the hydrophilic portion of emerin. Using this antibody, we have analyzed emerin expression in Emery-Dreifuss muscular dystrophy (EDMD) patients and controls, by immunocytochemistry, in skeletal muscle and skin, and by immunoblot, in peripheral blood mononuclear cells and lymphoblasts. Emerin was localized on the surfaces of nuclei in control skeletal muscle and skin but was absent or reduced in patient skeletal muscle, was absent from the skin of patients, and was expressed only in a few nuclei in a patient's mother. Immunoblot of peripheral blood cells from EDMD patients showed absence of the emerin band, altered-size emerin, or a protein of normal molecular mass but slightly reduced quantity. The diagnosis of X-linked EDMD is normally confirmed by genetic analysis of the STA gene coding for emerin. We propose immunocytochemical evaluation of emerin expression in skin biopsies as a sensitive and more convenient tool for diagnosing X-linked EDMD and, in particular, for distinguishing it from the autosomal dominant form. This technique may be applied to suspected EDMD patients, especially sporadic cases or those with incomplete clinical phenotype, and also suspected carriers. Immunoblot of peripheral blood cells is also useful, but it may not unequivocally identify carriers and some patients.