| Title: | Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease |
| Journal: | Nature Genetics |
| Published: | 10 Jun 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38858457/ |
| DOI: | https://doi.org/10.1038/s41588-024-01787-7 |
| URL: | https://www.nature.com/articles/s41588-024-01787-7.pdf |
| Citations: | 2 (2 in last 2 years) as of 8 Aug 2024 |
Publication 11888
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Abstract
Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified1,2. 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. 3,4). 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 activity5-7 - and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.</p>
14 Keywords
- Aged
- Case-Control Studies
- Exome
- Exome Sequencing
- Female
- Genetic Predisposition to Disease
- Humans
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
- Male
- Middle Aged
- Mutation
- Parkinson Disease
- Pedigree
- rab GTP-Binding Proteins
22 Authors
- Paul J. Hop
- Dongbing Lai
- Pamela J. Keagle
- Desiree M. Baron
- Brendan J. Kenna
- Maarten Kooyman
- Shankaracharya
- Cheryl Halter
- Letizia Straniero
- Rosanna Asselta
- Salvatore Bonvegna
- Alexandra I. Soto-Beasley
- Zbigniew K. Wszolek
- Ryan J. Uitti
- Ioannis Ugo Isaias
- Gianni Pezzoli
- Nicola Ticozzi
- Owen A. Ross
- Jan H. Veldink
- Tatiana M. Foroud
- Kevin P. Kenna
- John E. Landers
1 Application
| Application ID | Title |
|---|---|
| 48361 | Genome wide association analysis of Amyotrophic Lateral Sclerosis (ALS) |
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