Introduction Parkinson's Disease (PD) features debilitating motor symptoms, particularly gait and balance impairments inadequately managed by current therapies. Bassoon (BSN), a presynaptic active zone organizer, has been implicated in various neurological disorders. Here, we evaluate the impact of rare BSN mutations on motor symptoms in PD patients. Methods Our study included 110 PD patients carrying BSN mutations and 558 PD controls from a South Asian early onset PD cohort (onset <50 years). Variants with mean allele frequency (MAF) <0.1% were classified as "rare" (n=44). Clinical motor features were compared between variant carriers and non-carriers. Computational tools (CADD, PolyPhen-2, I-Mutant2.0, ConSurf) predicted deleteriousness, while GeneMANIA and STRING elucidated Bassoon's functional interactions. Results Patients carrying BSN variants exhibited significantly increased freezing of gait (FOG, p=0.026, Carmer's V=0.118), shuffling gait (SG, p=0.041, Carmer's V=0.111), and falls (p=0.028, Carmer's V=0.117). Rare BSN mutations clustered in the Bassoon C-terminal region (aa 3500-3800), threefold above expected frequency. Computational predictions identified seven likely pathogenic variants (P171L, A852T, P988A, R1015H, R2561H, R3400W, L3561P), with highest confidence for P171L (confirmed by AlphaMissense). Functional analyses implicated Bassoon in axonal transport, presynaptic proteostasis, and neurotransmitter release in dopaminergic/cholinergic neurons. Conclusion Our findings identify BSN mutations as a genetic risk factor for PD-related gait and balance dysfunction, highlighting Bassoon's role in neurotransmission. The link with Progressive Supranuclear Palsy phenotypes suggests Bassoon dysfunction could represent a convergence point between synucleinopathies and tauopathies.
Kukkle et al. (2025) studied this question.