RESUMEN
Early-onset Parkinson's disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty-eight mutation-positive individuals, available family members, and 62 mutation-negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.
Asunto(s)
Enfermedad de Parkinson/genética , Mutación Puntual/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Estudios de Casos y Controles , Análisis Mutacional de ADN , Exones/genética , Femenino , Eliminación de Gen , Frecuencia de los Genes/genética , Haplotipos , Homocigoto , Humanos , Desequilibrio de Ligamiento/genética , Masculino , LinajeRESUMEN
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.
Asunto(s)
Proteínas del Citoesqueleto/genética , Distonía/complicaciones , Distonía/genética , Glicoproteínas de Membrana/genética , Mutación/genética , Mioclonía/complicaciones , Mioclonía/genética , Alelos , Niño , Preescolar , Islas de CpG/genética , Metilación de ADN , Análisis Mutacional de ADN , Padre , Femenino , Genes Dominantes/genética , Impresión Genómica , Haplotipos/genética , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Penetrancia , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , SarcoglicanosRESUMEN
Early-onset parkinsonism is frequently reported in connection with mutations in the parkin gene. In this study, we present the results of extensive genetic screening for parkin mutations in 111 community-derived early-onset parkinsonism patients (age of onset <50 years) from Germany with an overall mutation rate of 9.0%. Gene dosage alterations represented 67% of the mutations found, underlining the importance of quantitative analyses of parkin. In summary, parkin mutations accounted for a low but significant percentage of early-onset parkinsonism patients in a community-derived sample.
