Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*

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Abstract
There is increasing evidence of genetic contribution to the pathogenesis of Parkinson's disease. The identification of mutations in the leucine-rich repeat kinase 2 (LRRK2) gene has shed new light on genetic variations responsible for autosomal dominantly inherited Parkinson's disease. In this analysis, the most comprehensive published so far, we screened a second large series comprising 53 families with Parkinson's disease for mutations in the LRRK2 gene by direct sequencing to further determine the frequency of the mutation and evaluate the clinical phenotype to establish a genotype/phenotype relation. For comparison, all novel and known mutations were investigated in a cohort of 337 patients with apparently sporadic Parkinson's disease and a cohort of 1200 control subjects using an ABI 7900 Allelic Detection system. We identified 7 more families with LRRK2 variations in the 53 families with Parkinson's disease. Four of these are novel amino acid substitutions (R793M, Q930R, S1096C, S1228T). Because of incomplete penetrance and possible phenocopies pathogenic relevance of the Q930R and S1096C mutations as well as for the previously described A3342G splice site mutation could not be established with certainty. The so far most common mutation (G2019) was not detected in our large cohort. Late onset and typical l-dopa responsive parkinsonian features were generally observed, often accompanied by impairment of executive functions and high interference values in neuropsychological testing, as well as sleeping disturbances but rare hallucinations. There were no abnormalities in electrophysiological investigations. Distinct intrafamily and interfamily differences could be observed, including the clinical presentation of diffuse Lewy body disease in one patient. The frequent finding of cerebral atrophy on MRI and less substantia nigra hyperechogenicity compared with idiopathic Parkinson's disease on transcranial ultrasound needs to be confirmed in further studies. Together with the findings obtained in 46 families in our first study, LRRK2 mutations, therefore, account for 13% of apparently autosomal dominant families in our population with varying but still generally typical clinical presentation of Parkinson's disease.