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.
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 Lrrk2p.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 Lrrk2p.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 Lrrk2p.R1441Cpatients 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.
Authors: Jennifer Kachergus; Ignacio F Mata; Mary Hulihan; Julie P Taylor; Sarah Lincoln; Jan Aasly; J Mark Gibson; Owen A Ross; Timothy Lynch; Joseph Wiley; Haydeh Payami; John Nutt; Demetrius M Maraganore; Krzysztof Czyzewski; Maria Styczynska; Zbigniew K Wszolek; Matthew J Farrer; Mathias Toft Journal: Am J Hum Genet Date: 2005-02-22 Impact factor: 11.025
Authors: Z K Wszolek; R F Pfeiffer; Y Tsuboi; R J Uitti; R D McComb; A J Stoessl; A J Strongosky; A Zimprich; B Müller-Myhsok; M J Farrer; T Gasser; D B Calne; D W Dickson Journal: Neurology Date: 2004-05-11 Impact factor: 9.910
Authors: Alexander Zimprich; Saskia Biskup; Petra Leitner; Peter Lichtner; Matthew Farrer; Sarah Lincoln; Jennifer Kachergus; Mary 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 Journal: Neuron Date: 2004-11-18 Impact factor: 17.173
Authors: S Goldwurm; A Di Fonzo; E J Simons; C F Rohé; M Zini; M Canesi; S Tesei; A Zecchinelli; A Antonini; C Mariani; N Meucci; G Sacilotto; F Sironi; G Salani; J Ferreira; H F Chien; E Fabrizio; N Vanacore; A Dalla Libera; F Stocchi; C Diroma; P Lamberti; C Sampaio; G Meco; E Barbosa; A M Bertoli-Avella; G J Breedveld; B A Oostra; G Pezzoli; V Bonifati Journal: J Med Genet Date: 2005-11 Impact factor: 6.318
Authors: Coro Paisán-Ruíz; Shushant Jain; E Whitney Evans; William P Gilks; Javier Simón; Marcel van der Brug; Adolfo López de Munain; Silvia Aparicio; Angel Martínez Gil; Naheed Khan; Janel Johnson; Javier Ruiz Martinez; David Nicholl; Itxaso Martí Carrera; Amets Saénz Pena; Rohan de Silva; Andrew Lees; José Félix Martí-Massó; Jordi Pérez-Tur; Nick W Wood; Andrew B Singleton Journal: Neuron Date: 2004-11-18 Impact factor: 17.173