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2.
J Med Genet ; 42(11): e65, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16272257

RESUMEN

BACKGROUND: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease. OBJECTIVE: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease. RESULTS: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years). CONCLUSIONS: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.


Asunto(s)
Mutación , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Alelos , Secuencia de Bases , Femenino , Efecto Fundador , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular
3.
Neurology ; 65(1): 87-95, 2005 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-16009891

RESUMEN

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación/genética , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Adolescente , Adulto , Edad de Inicio , Niño , Análisis Mutacional de ADN , ADN Complementario/análisis , ADN Complementario/genética , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Genoma/genética , Genotipo , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Mutación Missense , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/fisiopatología , Fenotipo , Polimorfismo Genético/genética , Homología de Secuencia de Aminoácido
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