A novel mutation in LRRK2 influences risk for Parkinson disease in the Maltese population

Abstract

Introduction: LRRK2 encodes Leucine-rich repeat kinase 2, one of the most common known autosomal dominant genetic causes of Parkinson disease (PD). Individuals with mutations in LRRK2 present with a phenotype and pathology similar to idiopathic, late onset PD. A number of mutations have been identified in this gene, however, the pathogenic nature of most mutations remains unclear. Materials and Methods: Next generation sequencing data from healthy individuals was mined for LRRK2 mutations present in the Maltese. A novel mutation (N618S) was identified and genotyped by PCR and RFLP in a PD case-control collection; 73 cases and 136 control samples from Malta collected as part of the Geoparkinson project. Odds Ratio (OR) with 95% confidence interval (CI) was determined using logistic regression. Results: The novel mutation identified was in exon 16 of LRRK2. The A>G change at c.1853 gives rise to a missense mutation: N618S. Minor allele frequency was found to be 0.03 in controls (n=136) and 0.06 in cases (n=73), giving an OR of 2.17 (95%CI: 0.82 - 5.74). Conclusions: The novel N618S mutation appears to increase risk for PD in the Maltese. Funding sources for this study: Data and samples were collected as part of the 5th framework (FP5) EU funded Geoparkinson study, project number QLK4‐CT‐1999‐01133. This work was supported by the MASTER it! Program (Malta); this scheme is co-funded by the ESF under Operational Program II-Cohesion Policy 2007-2013.