Novel LRRK2 mutations in Parkinsonism

Joanne Trinh, Ilaria Guella, Marna McKenzie, Emil K Gustavsson, Chelsea Szu-Tu, Maria Skaalum Petersen, Alex Rajput, Ali H, Rajput, Martin McKeown, Beom S Jeon, Jan O Aasly, Soraya Bardien, Matthew J. Farrer

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Genetic variability in leucine-rich repeat kinase 2 (LRRK2) has been implicated in Parkinson disease (PD). Six genetically-linked, pathogenic mutations clearly segregate with autosomal dominant Parkinsonism within multi-incident families. While these mutations all confer high genotypic risk of PD (odd's ratios up to 22.6) [ [1] ], two have significant population attributable risk and originate from a small number of ancestral founders; LRRK2 p.G2019S is best described in PD in Berber-Arabs and Ashkenazi Jews, whereas p.R1441G is frequent in PD in the Spanish Basque population. Appreciably more LRRK2 susceptibility variants confer lower genotypic risk (odd's ratios 0.62–4.48) and segregation with Parkinsonism within multi-incident families is more difficult to discern [ [2] ]. Nevertheless, independently and perhaps jointly these polymorphisms confer significant population attributable risks of PD, albeit a function of their population-specific minor allele frequencies [ 2 , 3 ]; LRRK2 p.M1646T and p.G2385R increase risk of PD in Caucasian or Asian patients respectively, whereas a protective haplotype (N551K-R1398H–K1432K) has been identified in both races. Several sequencing studies have identified additional LRRK2 variability which may also confer disease risk and inform protein structure–function relationships. Herein we report additional novel LRRK2 amino acid substitutions.
Original languageEnglish
Pages (from-to)1119-1121
Number of pages3
JournalParkinsonism & Related Disorders
Volume21
Issue number9
DOIs
Publication statusPublished - Sep 2015

Keywords

  • LRRK2 gene
  • Parkinson disease
  • MSA
  • PSP
  • disease
  • susceptibility
  • variants

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