LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8
- 30 October 2007
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 69 (18), 1737-1744
- https://doi.org/10.1212/01.wnl.0000278115.50741.4e
Abstract
Background: Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been found to cause typical, later-onset Parkinson disease (PD). Although G2019S is the most common mutation, other mutations have also been reported. It is critical to catalog the types of mutations found in LRRK2 that can cause PD, so as to provide insight regarding disease susceptibility and potential novel treatments. Methods: We performed a comprehensive study of all 51 exons of the LRRK2 gene in one PD patient from each of 88 multiplex PD families who had the highest family-specific multipoint lod score at the LRRK2 locus from a cohort of 430 PD families without the G2019S mutation. Results: Five families (5.7%) harbored what seem to be novel, pathogenic mutations (L1795F, I1192V, E10K, E334K, Q1111H). Three of these apparent mutations were in known, functional domains of the LRRK2 protein, where other studies have also identified disease producing mutations. However, two of the novel variants were found in the N-terminal region of LRRK2, where no pathogenic substitutions have yet been reported. Similar to previous studies, all subjects with an LRRK2 mutation had classic symptoms of PD and typical, later age at onset. Conclusions: We have identified five novel variants in LRRK2, with two of these in the N-terminal region of LRRK2, where no pathogenic substitutions have been previously reported. If confirmed to be causative, these mutations would broaden the potential mechanisms whereby mutations in LRRK2 result in Parkinson disease. GLOSSARY: AD = Alzheimer disease; cDNA = complementary DNA; COR = C terminal of Ras; Hisp = Hispanic; LRR = leucine-rich repeat; LRRK2 = leucine-rich repeat kinase 2 gene; MMSE = Mini-Mental State Examination; NS = nonsynonymous variant that is potentially disease producing; PD = Parkinson disease; Roc = Ras of complex; S = synonymous variant that is not likely to be pathogenic; UPDRS = Unified Parkinson’s Disease Rating Scale.Keywords
This publication has 30 references indexed in Scilit:
- Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicityHuman Molecular Genetics, 2007
- Leucine-rich repeat kinase 2: Relevance to Parkinson's diseaseThe International Journal of Biochemistry & Cell Biology, 2006
- Digenic parkinsonism: Investigation of the synergistic effects of PRKN and LRRK2Neuroscience Letters, 2006
- Mutations in DJ-1 are rare in familial Parkinson diseaseNeuroscience Letters, 2006
- Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease*Brain, 2005
- Lrrk2 pathogenic substitutions in Parkinson's diseaseneurogenetics, 2005
- LRRK2 Haplotype Analyses in European and North African Families with Parkinson Disease: A Common Founder for the G2019S Mutation Dating from the 13th CenturyAmerican Journal of Human Genetics, 2005
- Genetics of Parkinsonʼs diseaseCurrent Opinion in Neurology, 2005
- Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's DiseaseNeuron, 2004
- Genome Screen to Identify Susceptibility Genes for Parkinson Disease in a Sample without parkin MutationsAmerican Journal of Human Genetics, 2002