RESUMO
Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmission, suggesting a putative maternal imprinting mechanism. We present an apparently sporadic M-D case and two patients from an M-D family with seemingly autosomal recessive inheritance. In both families, we detected an SGCE mutation that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. Whereas, in the first family, RNA expression studies revealed expression of only the mutated allele in affected individuals and expression of the normal allele exclusively in unaffected mutation carriers, the affected individual of the second family expressed both alleles. In addition, we identified differentially methylated regions in the promoter region of the SGCE gene as a characteristic feature of imprinted genes. Using a rare polymorphism in the promoter region in a family unaffected with M-D as a marker, we demonstrated methylation of the maternal allele, in keeping with maternal imprinting of the SGCE gene. Loss of imprinting in the patient with M-D who had biallelic expression of the SGCE gene was associated with partial loss of methylation at several CpG dinucleotides.
Assuntos
Proteínas do Citoesqueleto/genética , Distonia/complicações , Distonia/genética , Glicoproteínas de Membrana/genética , Mutação/genética , Mioclonia/complicações , Mioclonia/genética , Alelos , Criança , Pré-Escolar , Ilhas de CpG/genética , Metilação de DNA , Análise Mutacional de DNA , Pai , Feminino , Genes Dominantes/genética , Impressão Genômica , Haplótipos/genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Penetrância , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SarcoglicanasRESUMO
Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.