High-Risk Parkinson’s Variant Discovered with Whole Genome and Exome Sequencing

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A potential landmark genetic association study for the neurodegenerative disorder Parkinson’s has uncovered a new risk variant. The team, which included scientists from the University Medical Center Utrecht, Indiana University School of Medicine, and UMass Chan Medical School, combined whole genome and exome sequencing data from 2184 familial Parkinson’s disease patients, resulting in the discovery of a specific mutation in a gene that encodes a small GTPase known as RAB32. In the Nature Genetics article, the researchers show that the toxicity of this variant is most probably mediated through the enhancement of activity for LRRK2, a known Parkinson’s disease target.

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Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease (2024)
Hop, Paul J.; Lai, Dongbing; Keagle, Pamela J.; Baron, Desiree M.; Kenna, Brendan J.; Kooyman, Maarten; Shankaracharya; Halter, Cheryl; Straniero, Letizia; Asselta, Rosanna; Bonvegna, Salvatore; Soto-Beasley, Alexandra I.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Isaias, Ioannis Ugo; Pezzoli, Gianni; Ticozzi, Nicola; Ross, Owen A.; Veldink, Jan H.; Foroud, Tatiana M.; Kenna, Kevin P.; Landers, John E.

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.

Link | PDF (Nature Genetics) [Open Access]