A novel TTBK2 missense variant causes loss of function and impaired protein phosphorylation: implications for spinocerebellar ataxia type 11

ABSTRACT: Spinocerebellar ataxia type 11 (SCA11) is a rare form of autosomal dominant cerebellar ataxia, characterized by a relatively slow progression and normal life expectancy. However, it is a highly debilitating disorder. In 2007, SCA11 was genetically linked to TTBK2, which encodes tau tubulin kinase 2 (TTBK2). Since then, only a few families and patients carrying TTBK2 truncating variants have been identified. TTBK2 missense variants were also reported but their pathogenic potential has not been ascertained. TTBK2 has several functions, including the regulation of proteins associated with neurodegeneration, microtubules, and ciliogenesis. Further research is necessary to fully elucidate the precise mechanisms through which TTBK2 variants may cause SCA11. In this study, we investigated the pathogenic mechanisms associated with a novel heterozygous missense variant located in the kinase domain of TTBK2 (NM_173500.4:c.625C>T; p.Leu209Phe), potentially linked to progressive cerebellar ataxia. Through functional studies conducted in a knock-in CRISPR/Cas9 cell model, we associated the variant TTBK2-L209F with reduced TTBK2 protein expression, disturbed cytoskeleton-associated proteins, and deficient kinase activity against TDP-43. Furthermore, our analysis of the phosphoproteome revealed potential impairments in gene regulation, protein degradation, and cytoskeleton-related pathways. Interestingly, altered levels of TGF-β signaling phosphoproteins were also associated with TTBK2-L209F, aligned with findings on other neurodegenerative disorders. These findings open new perspectives and insights into the molecular pathogenesis of SCA11. Moreover, our results underscore the significance of conducting functional studies to validate the impact of TTBK2 missense variants, particularly those located in the kinase domain.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Cerebellar Ataxia

SUBMITTER: Hugo Osorio  

LAB HEAD: Mariana Santos

PROVIDER: PXD056662 | Pride | 2025-12-22

REPOSITORIES: Pride