R869C mutation in molecular motor KIF17 gene is involved in dementia with Lewy bodies.

Introduction the GBA-N370S mutation is one of the most frequent risk factors for dementia with Lewy bodies (DLB) and Parkinson's disease (PD). We looked for genetic variations that contribute to the outcome in N370S-carriers, whether PD or DLB. Methods Whole-genome sequencing of 95 Ashkenazi-N370S-carriers affected with either DLB (n = 19) or PD (n = 76) was performed, and 564 genes related to dementia and PD analyzed. Results We identified enrichment of linked alleles in PINK1 locus in DLB patients (false discovery rate P = .0412). Haplotype analysis delineated 1.8 Mb interval encompassing 29 genes and 87 unique variants, of them, KIF17-R869C received the highest functional prediction score (Combined Annotation Dependent Depletion = 34). Its frequency was significantly higher in 26 DLB-N370S-carriers compared to 140 PD-N370S-carriers (odds ratio [OR] = 33.4 P = .001, and OR = 70.2 when only heterozygotes were included). Discussion Because KIF17 was shown to be important for learning and memory in mice, our data further suggest, for the first time, its involvement in DLB, and possibly in human dementia.