RESUMEN
BACKGROUND: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have become the most common known cause for developing Parkinson's disease. The frequency of mutations described in the literature varies widely depending on the population studied with most reports focusing only on screening for the most common G2019S mutation in exon 41. METHODS: In this study seven exons (19, 24, 25, 31, 35, 38, and 41) in LRRK2 where mutations have been reported were screened in 230 unselected Parkinson's disease patients using denaturing high-performance liquid chromatography. RESULTS: The sequencing of samples with heteroduplex profiles revealed five novel and two known intronic sequence variants. In our cohort, we were unable to detect any of the known mutations in these exons or identify novel mutations within the LRRK2 gene. CONCLUSIONS: Therefore, despite the availability of diagnostic LRRK2 genetic testing it is unlikely to yield a positive result in this population.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/normas , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Secuencia de Bases/genética , Canadá/epidemiología , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Análisis Mutacional de ADN/normas , Análisis Mutacional de ADN/tendencias , Exones/genética , Femenino , Pruebas Genéticas/tendencias , Genotipo , Humanos , Intrones/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Mutación/genética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Valor Predictivo de las PruebasRESUMEN
Myoclonus-dystonia syndrome (MDS) is a disorder for which the major cause appears to be mutations in the epsilon-sarcoglycan gene (SGCE). The authors have now performed mutation screening in 22 affected individuals from seven families with findings of typical MDS. A novel 5-bp deletion in exon 7 of the gene in one family and the previously reported R102X nonsense mutation in exon 3 in two other families were identified. Mutations in the SGCE gene were found in the minority of families screened in this series.
Asunto(s)
Proteínas del Citoesqueleto/genética , Trastornos Distónicos/genética , Glicoproteínas de Membrana/genética , Mioclonía/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Exones/genética , Femenino , Mutación del Sistema de Lectura , Frecuencia de los Genes , Humanos , Lactante , Masculino , Fenotipo , Sarcoglicanos , Eliminación de SecuenciaRESUMEN
OBJECTIVE: Inherited myoclonus-dystonia (IMD) is a new term for an autosomal dominant disorder characterized by myoclonus and dystonia. Recently, IMD was linked to a region on chromosome 11q23 with two different mutations identified in the D2 dopamine receptor gene and linked to chromosome 7q with five different loss-of-function mutations identified in the epsilon-sarcoglycan gene. METHODS: These two regions and genes were excluded in a large Canadian family with IMD in whom 13 individuals are affected. A 25-cM genome scan of this large family with 32 individuals was performed. RESULTS: Two-point linkage analysis revealed a maximum lod score of 3.5 (recombination fraction 0.00; affected only) for the microsatellite marker GATA185C06-18 and a multipoint lod score of 3.9 across the 18p11 region. Haplotype analysis demonstrates that all the affected individuals shared a common haplotype between markers D18S1132 and D18S843 that defines the disease gene within a span of 16.9 cM. CONCLUSIONS: These findings indicate that a novel IMD gene exists on chromosome 18p11.
Asunto(s)
Cromosomas Humanos Par 18/genética , Distonía/genética , Ligamiento Genético/genética , Mioclonía/genética , Niño , Cromosomas Humanos Par 7/genética , Femenino , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Mutación/genética , Linaje , Receptores de Dopamina D2/genética , SíndromeRESUMEN
PURPOSE: Two large Canadian kindreds appearing to segregate febrile convulsions as an autosomal dominant trait were evaluated for linkage to three known FC loci, as well as other epilepsy loci. METHODS: Members of the two families were genotyped with microsatellite markers linked to the previously identified febrile convulsion loci, FEB1, FEB2, and GEFS+, and we performed two-point linkage analyses by assuming an autosomal dominant mode of inheritance. RESULTS: We report the exclusion of the FC trait in our families to FEB1 on 8q13-21 and to a second febrile convulsion locus on 19p13. Furthermore, we also excluded the GEFS+ locus on 19q13.1 as the cause of febrile convulsions in both kindreds. Microsatellite markers linked to juvenile myoclonic epilepsy (EJM1), benign neonatal familial convulsions EBN1 and EBN2, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), idiopathic generalized epilepsy (EGI), progressive myoclonic epilepsy of Unverricht-Lundborg (EPM1), and partial epilepsy with auditory features (EPT), were also excluded as potential loci linked to the FC trait in our families. CONCLUSIONS: These findings favor considerable genetic heterogeneity for febrile convulsions.
