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Matthew J Farrer - One of the best experts on this subject based on the ideXlab platform.
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lrrk2 and Parkinson disease
JAMA Neurology, 2010Co-Authors: Justus C Dachsel, Matthew J FarrerAbstract:Objectives To review the molecular genetics and functional biology of leucine-rich repeat kinase 2 ( LRRK2 ) in Parkinsonism and to summarize the opportunities and challenges to develop interventions for Parkinson disease (PD) based on this genetic insight. Data Sources Publications cited are focused on LRRK2 biology between 2004 and March 2009. Study Selection Literature selected was based on original contributions, seminal observations, and thoughtful reviews. Data Extraction Unless stated otherwise, data was primarily abstracted from peer-reviewed literature appearing on PubMed. Data Synthesis Genetic mutations that predispose PD are diagnostically useful in early or atypical presentations. The molecular pathways identified suggest therapeutic interventions for Lrrk2 and idiopathic PD and the rationale and opportunity to develop physiologically relevant biomarkers and experimental models with which to test them. Conclusions Both affected and asymptomatic LRRK2 carriers now provide the opportunity to define the natural history of PD. This includes the frequency, penetrance, and rate of motor symptoms, nonmotor comorbidities, and their associated biomarkers.
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LRRK2 and Parkinsons disease in Norway
2007Co-Authors: Kristoffer Haugarvoll, Matthew J Farrer, Mathias Toft, Owen A. Ross, Jan O AaslyAbstract:Objectives – Mutations in the LRRK2 gene have been associated with both familial and sporadic late-onset Parkinsons disease. A large number of mutations in this gene have been identified; however, for many of these variants, the pathogenicity and relative frequency are unknown. Herein, we investigate the frequency of a number of recently identified LRRK2 mutations in Norway. Methods – We genotyped eight putatively pathogenic LRRK2 mutations (R793M, R1067Q, I1371V, IVS31+3 A>G, M1869T, R1941H, T2356I and G2385R) in a series of 433 patients with Parkinsons disease and 587 controls from Norway. An intronic polymorphism previously reported to be associated with disease susceptibility was also examined (rs10506151). Results – The Lrrk2 R793M substitution was found in two healthy individuals. No other LRRK2 mutations were identified in the Norwegian population, and furthermore no association was observed between rs10506151 and Parkinson sd isease (P = 0.41). Conclusions – LRRK2 mutations other than the Lrrk2 G2019S mutation are rare in Norway. Our results indicate that the Lrrk2 R793M substitution is most likely a rare polymorphism.
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Clinical Heterogeneity of the LRRK2 G2019S Mutation
JAMA Neurology, 2006Co-Authors: Spiridon Papapetropoulos, Matthew J Farrer, Mathias Toft, Owen A. Ross, Carlos Singer, Joseph L. Johnson, Deborah C. MashAbstract:Background Several pathogenic mutations have been reported in the leucine-rich repeat kinase 2 gene ( LRRK2 ) that cause Parkinsonism. The “common” LRRK2 G2019S kinase domain substitution has been reported to account for approximately 5% of familial and 1% of sporadic Parkinson disease. Objective To observe the clinical heterogeneity presented by LRRK2 kinase mutation carriers. Design, Setting, and Participants We screened 130 patients with pathologically confirmed Parkinson disease and 85 controls for 3 LRRK2 kinase domain pathogenic substitutions: I2012T, G2019S, and I2020T. Main Outcome Measures Detailed clinical phenotypes for individuals who screened positive for LRRK2 mutations. Results Five LRRK2 G2019S carriers were identified, of whom 4 had Parkinson disease (clinically and pathologically confirmed), and the fifth was a control subject who died at age 68 years after an acute myocardial infarction with no evidence of neurodegenerative abnormalities. There was no evidence of the I2012T or I2020T mutation in these participants. Conclusions The underlying disease mechanisms of LRRK2 G2019S–associated Parkinsonism are similar to those of typical Parkinson disease. The identification of a control subject raises important questions concerning genetic diagnosis and counseling.
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high resolution whole genome association study of Parkinson disease
American Journal of Human Genetics, 2005Co-Authors: Demetrius M Maraganore, Matthew J Farrer, Mariza De Andrade, Timothy G Lesnick, Kari J Strain, Walter A Rocca, P Krishna V Pant, Kelly A Frazer, Dennis G BallingerAbstract:We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P
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lrrk2 mutations in Parkinson disease
Neurology, 2005Co-Authors: Matthew J Farrer, Kari J Strain, Jeremy T Stone, Ignacio F Mata, Sarah Lincoln, Jennifer M Kachergus, Mary M Hulihan, Demetrius M MaraganoreAbstract:To determine the frequency of LRRK2 mutations in idiopathic Parkinson disease (PD), the authors studied 786 PD probands, 32 affected siblings, 1,044 unaffected siblings, and 278 unrelated controls. The authors designed allelic discrimination assays for nine LRRK2 mutations and identified these in six probands with PD, one affected sibling, one unaffected sibling, and one unrelated control. Thus LRRK2 mutations only rarely cause idiopathic PD.
L Fananapazir - One of the best experts on this subject based on the ideXlab platform.
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identification of a gene responsible for familial wolff Parkinson white syndrome
The New England Journal of Medicine, 2001Co-Authors: Michael H Gollob, Martin S Green, Anthony S L Tang, T Gollob, Akihiko Karibe, Ali Hassan As, Ferhaan Ahmad, R Lozado, Gopi Shah, L FananapazirAbstract:Background The Wolff-Parkinson-White syndrome, with a prevalence in Western countries of 1.5 to 3.1 per 1000 persons, causes considerable morbidity and may cause sudden death. We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder. Methods We studied 70 members of the two families (57 in Family 1 and 13 in Family 2). The subjects underwent 12-lead electrocardiography and two-dimensional echocardiography. Genotyping mapped the gene responsible to 7q34-q36, a locus previously identified to be responsible for an inherited form of Wolff-Parkinson-White syndrome. Candidate genes were identified, sequenced, and analyzed in normal and affected family members to identify the disease-causing gene. Results A total of 31 members (23 from Family 1 and 8 from Family 2) had the Wolff-Parkinson-White syndrome. Affected members of both families had ventricular preexcitation with conduction abnormalities and cardiac hypertrophy. The maximal combined two-point lod score was 9.82 at a distance of 5 cM from marker D7S636, which confirmed the linkage of the gene in both families to 7q34-q36. Haplotype analysis indicated that there were no alleles in common in the two families at this locus, suggesting that the two families do not have a common founder. We identified a missense mutation in the gene that encodes the y2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. Conclusions The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.
Jennifer M Kachergus - One of the best experts on this subject based on the ideXlab platform.
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vps35 mutations in Parkinson disease
American Journal of Human Genetics, 2011Co-Authors: Carles Vilarinoguell, Owen A. Ross, Justus C Dachsel, Sarah Lincoln, Jennifer M Kachergus, Christian Wider, Alexandra I Sotoortolaza, Stephanie A Cobb, Greggory J Wilhoite, Justin A BaconAbstract:The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive Parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
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lrrk2 r1441c Parkinsonism is clinically similar to sporadic Parkinson disease
Neurology, 2008Co-Authors: Kristoffer Haugarvoll, Owen A. Ross, Karen Nuytemans, Jennifer M Kachergus, Rosa Rademakers, J M Gibson, Carles Gaig, E TolosaAbstract:Objective: Leucine-rich repeat kinase 2 ( LRRK2 ) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C. Methods: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. Results: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S Parkinsonism. The mean age at onset for Parkinsonism was 60 years, range 30–79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation. Conclusions: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S Parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis. GLOSSARY: COR = C-terminal of Roc; GTPase = guanosine triphosphatase; LBD = Lewy body disease; PD = Parkinson disease; SNPs = single nucleotide polymorphisms.
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lrrk2 mutations in Parkinson disease
Neurology, 2005Co-Authors: Matthew J Farrer, Kari J Strain, Jeremy T Stone, Ignacio F Mata, Sarah Lincoln, Jennifer M Kachergus, Mary M Hulihan, Demetrius M MaraganoreAbstract:To determine the frequency of LRRK2 mutations in idiopathic Parkinson disease (PD), the authors studied 786 PD probands, 32 affected siblings, 1,044 unaffected siblings, and 278 unrelated controls. The authors designed allelic discrimination assays for nine LRRK2 mutations and identified these in six probands with PD, one affected sibling, one unaffected sibling, and one unrelated control. Thus LRRK2 mutations only rarely cause idiopathic PD.
Demetrius M Maraganore - One of the best experts on this subject based on the ideXlab platform.
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high resolution whole genome association study of Parkinson disease
American Journal of Human Genetics, 2005Co-Authors: Demetrius M Maraganore, Matthew J Farrer, Mariza De Andrade, Timothy G Lesnick, Kari J Strain, Walter A Rocca, P Krishna V Pant, Kelly A Frazer, Dennis G BallingerAbstract:We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P
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lrrk2 mutations in Parkinson disease
Neurology, 2005Co-Authors: Matthew J Farrer, Kari J Strain, Jeremy T Stone, Ignacio F Mata, Sarah Lincoln, Jennifer M Kachergus, Mary M Hulihan, Demetrius M MaraganoreAbstract:To determine the frequency of LRRK2 mutations in idiopathic Parkinson disease (PD), the authors studied 786 PD probands, 32 affected siblings, 1,044 unaffected siblings, and 278 unrelated controls. The authors designed allelic discrimination assays for nine LRRK2 mutations and identified these in six probands with PD, one affected sibling, one unaffected sibling, and one unrelated control. Thus LRRK2 mutations only rarely cause idiopathic PD.
Kristoffer Haugarvoll - One of the best experts on this subject based on the ideXlab platform.
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lrrk2 r1441c Parkinsonism is clinically similar to sporadic Parkinson disease
Neurology, 2008Co-Authors: Kristoffer Haugarvoll, Owen A. Ross, Karen Nuytemans, Jennifer M Kachergus, Rosa Rademakers, J M Gibson, Carles Gaig, E TolosaAbstract:Objective: Leucine-rich repeat kinase 2 ( LRRK2 ) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C. Methods: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. Results: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S Parkinsonism. The mean age at onset for Parkinsonism was 60 years, range 30–79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation. Conclusions: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S Parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis. GLOSSARY: COR = C-terminal of Roc; GTPase = guanosine triphosphatase; LBD = Lewy body disease; PD = Parkinson disease; SNPs = single nucleotide polymorphisms.
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LRRK2 and Parkinsons disease in Norway
2007Co-Authors: Kristoffer Haugarvoll, Matthew J Farrer, Mathias Toft, Owen A. Ross, Jan O AaslyAbstract:Objectives – Mutations in the LRRK2 gene have been associated with both familial and sporadic late-onset Parkinsons disease. A large number of mutations in this gene have been identified; however, for many of these variants, the pathogenicity and relative frequency are unknown. Herein, we investigate the frequency of a number of recently identified LRRK2 mutations in Norway. Methods – We genotyped eight putatively pathogenic LRRK2 mutations (R793M, R1067Q, I1371V, IVS31+3 A>G, M1869T, R1941H, T2356I and G2385R) in a series of 433 patients with Parkinsons disease and 587 controls from Norway. An intronic polymorphism previously reported to be associated with disease susceptibility was also examined (rs10506151). Results – The Lrrk2 R793M substitution was found in two healthy individuals. No other LRRK2 mutations were identified in the Norwegian population, and furthermore no association was observed between rs10506151 and Parkinson sd isease (P = 0.41). Conclusions – LRRK2 mutations other than the Lrrk2 G2019S mutation are rare in Norway. Our results indicate that the Lrrk2 R793M substitution is most likely a rare polymorphism.
