Parkinson's disease: from monogenic forms to genetic susceptibility factors
Suzanne Lesage,Alexis Brice +1 more
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TLDR
Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.Abstract:
Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the alpha-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the beta-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.read more
Citations
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References
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Mutation in the α-synuclein gene identified in families with Parkinson's disease
Mihael H. Polymeropoulos,Christian Lavedan,Elisabeth Leroy,Susan E. Ide,Anindya Dehejia,Amalia Dutra,Brian L. Pike,Holly Root,Jeffrey Rubenstein,Rebecca Boyer,Edward S. Stenroos,Settara C. Chandrasekharappa,Aglaia Athanassiadou,Theodore Papapetropoulos,William G. Johnson,Alice Lazzarini,Roger C. Duvoisin,Giuseppe Di Iorio,Lawrence I. Golbe,Robert L. Nussbaum +19 more
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Journal ArticleDOI
α-Synuclein Locus Triplication Causes Parkinson's Disease
Andrew B. Singleton,Matthew J. Farrer,Joshua C. Johnson,Amanda Singleton,Stephen Hague,Jennifer M. Kachergus,Mary M. Hulihan,Terhi Peuralinna,Amalia Dutra,Robert L. Nussbaum,Sarah Lincoln,Anthony Crawley,Melissa Hanson,Demetrius M. Maraganore,Charles H. Adler,Mark R. Cookson,Manfred D. Muenter,Melisa J. Baptista,David Miller,J. Blancato,John Hardy,Katrina Gwinn-Hardy +21 more
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Rejko Krüger,Wilfried Kuhn,Thomas Müller,Dirk Woitalla,Manuel B. Graeber,Sigfried Kösel,Horst Przuntek,Jörg T. Epplen,Ludger Schöls,Olaf Riess +9 more
Journal ArticleDOI
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Alexander Zimprich,Alexander Zimprich,Saskia Biskup,Petra Leitner,Peter Lichtner,Matthew J. Farrer,Sarah Lincoln,Jennifer M. Kachergus,Mary M. Hulihan,Ryan J. Uitti,Donald B. Calne,A. Jon Stoessl,Ronald F. Pfeiffer,Nadja Patenge,Iria Carballo Carbajal,Peter Vieregge,Friedrich Asmus,Bertram Müller-Myhsok,Dennis W. Dickson,Thomas Meitinger,Tim M. Strom,Zbigniew K. Wszolek,Thomas Gasser +22 more
TL;DR: High-resolution recombination mapping and candidate gene sequencing in 46 families found six disease-segregating mutations in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2), which may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
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