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LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8

From Cincinnati Children’s Hospital Medical Center, Cincinnati, OH (W.C.N., V.E.E., M.W.P., D.K.M.); University of Cincinnati School of Medicine, Cincinnati, OH (W.C.N.); Indiana University Medical Center, Indianapolis, IN (N.P., C.A.H., T.F.); University of Rochester, Rochester, NY (A.R.); University of California, San Diego, La Jolla, CA (C.W.S.); and VA San Diego Healthcare System, San Diego, CA (C.W.S.).

Address correspondence and reprint requests to Dr. William C. Nichols, Associate Professor of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229 bill.nichols{at}cchmc.org

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.

Editorial, see page 1732

e-Pub ahead of print on September 5, 2007, at www.neurology.org.

Supported by R01 NS37167, MO1 RR-00750, and the National Cell Repository for Alzheimer’s Disease (U24 AG021886).

Disclosure: The author reports no conflicts of interest.

Received December 15, 2006. Accepted in final form February 28, 2007.

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