Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. ). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD-LRRK2 kinase activity-and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250361PMC
http://dx.doi.org/10.1038/s41588-024-01787-7DOI Listing

Publication Analysis

Top Keywords

familial parkinson's
8
parkinson's disease
8
familial cases
8
rab32
5
systematic rare
4
rare variant
4
variant analyses
4
analyses identify
4
identify rab32
4
rab32 susceptibility
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!