Genetic variability at the PARK16 locus
Résumé
Parkinson's disease is a complex neurodegenerative disease whose hallmark pathological features are loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have successfully been identified through linkage analyses. To identify susceptibility loci for idiopathic Parkinson's disease, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harbouring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases in addition to performing an association study in a case-control cohort from the UK. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (Pvalue = 0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation (CNV) analyses have yet been performed within this recently identified locus. We concluded that although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses in these genes within different populations are required in order to examine its biochemical role in the disease process.
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