The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease

Background: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson disease (PD) identified to date, and have been implicated in both familial and sporadic forms of the disease. The G2019S change in LRRK2 exon 41 has been associated with disease at varying frequencies in Asian, European, North American, and North African populations, and is particularly prevalent among Ashkenazi Jews. Methods: We assessed the occurrence of the LRRK2 G2019S, I2012T, I2020T, and R1441G/C/H mutations in our cohort of Jewish Israeli patients with PD, and determined the LRRK2 haplotypes in 76 G2019S-carriers detected and in 50 noncarrier Ashkenazi patients, using six microsatellite markers that span the entire gene. Results: Only the G2019S mutation was identified among our patients with PD, 14.8% in the Ashkenazi and 2.7% in the non-Ashkenazi patients, and in 26% and 10.6% of the Ashkenazi familial and apparently sporadic cases. The carrier frequencies in the Ashkenazi and non-Ashkenazi control samples were 2.4% and 0.4%. A common shared haplotype was detected in all non-Ashkenazi and half-Ashkenazi carriers and in all full-Ashkenazi carriers tested, except two. Women and patients with a positive family history of PD were significantly over-represented among the G2019S mutation carriers. Age at disease onset was similar in carriers and noncarriers. Conclusions: Our data suggest that the LRRK2 G2019S mutation plays an important role in the causality of familial and sporadic Parkinson disease (PD) in Israel and that gender affects its frequency among patients. Although testing symptomatic patients may help establish the diagnosis of PD, the value of screening asymptomatic individuals remains questionable until the penetrance and age-dependent risk of this mutation are more accurately assessed, and specific disease prevention or modifying interventions become available. GLOSSARY: LRRK2 = leucine-rich repeat kinase 2; PD = Parkinson disease.

[1]  P. Pollak,et al.  LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. , 2006, The New England journal of medicine.

[2]  A. Mosley,et al.  A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations , 2005, Neurology.

[3]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[4]  Hong Chen,et al.  Bioremediation potential of spirulina: toxicity and biosorption studies of lead. , 2005, Journal of Zhejiang University. Science. B.

[5]  E. Tolosa,et al.  LRRK2 mutations in Spanish patients with Parkinson disease: frequency, clinical features, and incomplete penetrance. , 2006, Archives of neurology.

[6]  Y. Agid,et al.  G2019S LRRK2 mutation in French and North African families with Parkinson's disease , 2005, Annals of neurology.

[7]  M. Canesi,et al.  The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson’s disease and originates from a common ancestor , 2005, Journal of Medical Genetics.

[8]  Leonard Petrucelli,et al.  Molecular pathogenesis of Parkinson disease. , 2005, Archives of neurology.

[9]  A. Dürr,et al.  LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. , 2005, American journal of human genetics.

[10]  Tatiana Foroud,et al.  Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease , 2005, The Lancet.

[11]  Janel O. Johnson,et al.  Clinical and positron emission tomography of Parkinson's disease caused by LRRK2 , 2005, Annals of neurology.

[12]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[13]  Kazuko Hasegawa,et al.  An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family , 2005, Annals of neurology.

[14]  Lue Ping Zhao,et al.  A method for the assessment of disease associations with single-nucleotide polymorphism haplotypes and environmental variables in case-control studies. , 2003, American journal of human genetics.

[15]  Vincenzo Bonifati,et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease , 2005, The Lancet.

[16]  M. Toft,et al.  Parkinson's disease: the genetics of a heterogeneous disorder , 2006, European journal of neurology.

[17]  J. Nutt,et al.  LRRK2 G2019S in families with Parkinson disease who originated from Europe and the Middle East: evidence of two distinct founding events beginning two millennia ago. , 2006, American journal of human genetics.

[18]  Christine Klein,et al.  LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. , 2006, The New England journal of medicine.

[19]  J. Hughes,et al.  Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. , 1992, Journal of neurology, neurosurgery, and psychiatry.

[20]  M. Farrer,et al.  Lrrk2 pathogenic substitutions in Parkinson's disease , 2005, Neurogenetics.

[21]  Andrew B West,et al.  Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Farrer,et al.  Clinical and pathologic features of families with LRRK2-associated Parkinson's disease. , 2006, Journal of neural transmission. Supplementum.

[23]  K. Marder,et al.  Frequency of LRRK2 mutations in early- and late-onset Parkinson disease , 2006, Neurology.

[24]  A. Brice.  Genetics of Parkinson's disease: LRRK2 on the rise. , 2005, Brain : a journal of neurology.

[25]  J. Nutt,et al.  Validity and utility of a LRRK2 G2019S mutation test for the diagnosis of Parkinson's disease. , 2006, Genetic testing.

[26]  J. Nutt,et al.  Parkinson's disease and LRRK2: Frequency of a common mutation in U.S. movement disorder clinics , 2006, Movement disorders : official journal of the Movement Disorder Society.

[27]  P. V. van Haastert,et al.  Roc, a Ras/GTPase domain in complex proteins. , 2003, Biochimica et biophysica acta.

[28]  G. Rennert,et al.  RNASEL Mutation Screening and Association Study in Ashkenazi and Non-Ashkenazi Prostate Cancer Patients , 2006, Cancer Epidemiology Biomarkers & Prevention.

[29]  Mathias Toft,et al.  Clinical features of LRRK2‐associated Parkinson's disease in central Norway , 2005, Annals of neurology.

[30]  Timothy Lynch,et al.  Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. , 2005, American journal of human genetics.

[31]  G. Wooten,et al.  Are men at greater risk for Parkinson’s disease than women? , 2004, Journal of Neurology, Neurosurgery & Psychiatry.

[32]  M. Farrer,et al.  Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries , 2006, Movement disorders : official journal of the Movement Disorder Society.

[33]  Nicholas W Wood,et al.  A common LRRK2 mutation in idiopathic Parkinson's disease , 2005, The Lancet.