Objective: To investigate the mutations of the BSN gene in patients with multiple system atrophy (MSA).

Background: We have reported some mutations in the bassoon (BSN) gene in cases with familial progressive supranuclear palsy (PSP) like syndrome characterized by the 3-repeat and 4-repeat tauopathy [1]. It has been suggested that “bassoon proteinopathy” drives neurodegeneration in several diseases including MSA [2], multiple sclerosis [3], amyotrophic lateral sclerosis [4], Huntington’s disease [5] and juvenile Parkinson’s disease [6].

Method: We included the patients who met the second consensus criteria for probable MSA. The variants of the BSN gene were detected using the next-generation sequencer. Missense variants were screened with gnomAD and HGVD to identify the rare variants (minor allele frequency < 0.01).

Results: Ninety-four patients (57 females and 37 males) with MSA were analyzed. The mean age at onset was 59.9±8.9 years (range 37-78 years). The cerebellar phenotype (MSA-C) was 60.4% (57/94). We found the 8 rare missense variants including c.1726T>C (p.S576P), c.5021C>G (p.P1674R), c.7541C>G (p.A2514G), c.7649G>A (p.R2550H), c.7783C>T (p.R2595C), c.9436C>T (p.R3146C), c.10823A>C (p.Q3608P) and c.10880G>T (p.G3627V) of BSN gene in 9.6% (9/94) cases. One patient harbors the two missense mutations (p.S576P and p.P1674R). Three patients harbor the p.G3627V mutation that we have reported in sporadic PSP [1].

Conclusion: We found the rare missense variants of the BSN gene in the patients with MSA. The pathogenicity of their mutations should be further investigated.

References: [1] Yabe I, Yaguchi H, Kato Y, et al. Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome. Sci Rep. 2018;8(1):819. [2] Hashida H, Goto J, Zhao N, et al. Cloning and mapping of ZNF231, a novel brain-specific gene encoding neuronal double zinc finger protein whose expression is enhanced in a neurodegenerative disorder, multiple system atrophy (MSA). Genomics. 1998;54(1):50-58. [3] Schattling B, Engler JB, Volkmann C, et al. Bassoon proteinopathy drives neurodegeneration in multiple sclerosis. Nat Neurosci. 2019;22(6):887-896. [4] Deshpande D, Higelin J, Schoen M, et al. Synaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses. Front Cell Neurosci. 2019;13:256. [5] Huang TT, Smith R, Bacos K, et al. No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease. Acta Neuropathol Commun. 2020;8(1):77. [6] Hoffmann-Conaway S, Brockmann MM, Schneider K, et al. Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice. Elife. 2020;9:e56590.

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