RIC3 – Parkinson Disease

RIC3 (HGNC:30338) was implicated in autosomal-dominant Parkinson disease (PD) through whole exome sequencing in a 14-member Indian pedigree showing non-motor symptoms. A heterozygous c.169C>A (p.Pro57Thr) variant segregated with disease in two affected cousins by targeted sequencing (PMID:27055476), and an additional c.502G>C (p.Val168Leu) variant was observed in a separate PD case (PMID:27055476). Large replication analyses, including a Han Chinese cohort of 218 patients (PMID:28606768) and a French-Canadian/French series of 535 patients and 527 controls (PMID:28153381), detected no enrichment of RIC3 variants, disputing the initial association.

Functional studies in PC12-derived neurons demonstrated a dominant-negative effect of RIC3 mutants, with reduced α7 nicotinic acetylcholine receptor (CHRNA7) membrane localization and decreased colocalization by confocal imaging (PMID:27055476). Although these in vitro assays reveal a potential mechanism for cholinergic dysregulation, the lack of consistent genetic association in diverse populations warrants a disputed classification for RIC3 in PD. Future large-scale studies in underrepresented ancestries are needed before RIC3 variants can be considered in clinical PD testing.

References

• Journal of medical genetics • 2016 • Evidence of mutations in RIC3 acetylcholine receptor chaperone as a novel cause of autosomal-dominant Parkinson's disease with non-motor phenotypes. PMID:27055476
• Neuroscience letters • 2017 • Genetic analysis of the RIC3 gene in Han Chinese patients with Parkinson's disease. PMID:28606768
• Neurobiology of aging • 2017 • RIC3 variants are not associated with Parkinson's disease in French-Canadians and French. PMID:28153381

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