Parkinson's disease (PD) is a neurodegenerative syndrome with diverse biological drivers, where gait and balance dysfunction remain among the most disabling and least understood symptoms. Bassoon (BSN), a presynaptic active-zone organizer, has been implicated in various parkinsonian disorders. Here, we report the impact of BSN mutations on motor symptoms, especially gait-related symptoms, in PD patients. Our study included 110 patients carrying BSN mutations in a cohort of 668 South Asian early-onset PD (age of onset < 50 years). Clinical motor features were compared between variant carriers and noncarriers. Computational tools (CADD, PolyPhen-2, I-Mutant2.0 and ConSurf) predicted deleteriousness of individual mutations, whereas GeneMANIA and STRING speculated Bassoon's functional interactions. Subjects carrying BSN variants exhibited significantly increased burden of motor-related symptoms (p = 0.036). Freezing of gait (FOG) and shuffling gait (SG) were significantly more prevalent in BSN mutation carriers (p = 0.03). Presence of BSN mutation correlated with an increased disease stage, an effect driven by FOG and SG (p = 0.012). Rare BSN mutations (MAF < 0.1%) clustered in the Bassoon C-terminal region (aa 3500-3800), at a threefold frequency than expected (p < 0.01), implying a hotspot. In silico analysis identified seven likely pathogenic variants (P171L, A852T, P988A, R1015H, R2561H, R3400W and L3561P). Predictive analyses implicated BSN in axonal transport, presynaptic proteostasis and neurotransmitter release in dopaminergic/cholinergic neurons. Our findings put forth BSN mutations as a potential genetic risk factor for PD-related motor and gait dysfunction, warranting further research in this respect.
Kukkle et al. (Sun,) studied this question.
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