Abstract
Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of 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 been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, 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 harboring 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, and also conducted an association study in a case–control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=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 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 within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.
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Acknowledgements
We thank all patients who participated in this study and all families who supported the donation of tissue for research. We also thank The Medical Research Council (MRC; HH: MRC fellowships G108/638 and G0802760 and JH: start-up funds) and The Michael J Fox Foundation (HH and CPR) for support. This study was also supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre. MAN and ABS were partly supported in this research by the Intramural Research Program of the NIH, National Institute on Aging (AG000957-07 (2009) Assessment of Candidate Loci in Neurological diseases).
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Tucci, A., Nalls, M., Houlden, H. et al. Genetic variability at the PARK16 locus. Eur J Hum Genet 18, 1356–1359 (2010). https://doi.org/10.1038/ejhg.2010.125
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DOI: https://doi.org/10.1038/ejhg.2010.125
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