TTBK2 and Spinocerebellar Ataxia Type 11

Recent studies robustly support an association between variants in TTBK2 and spinocerebellar ataxia type 11, a rare neurodegenerative disorder characterized by early-onset cerebellar ataxia, dysarthria, and abnormal movement. The cumulative clinical evidence spans multiple independent case reports and pedigree analyses that consistently demonstrate autosomal dominant inheritance and segregation of pathogenic variants (PMID:27165044, PMID:37848700).

Genetic evidence derives from several families, including a Danish family with a de novo frameshift mutation wherein the affected proband’s two sons carried the variant (PMID:27165044) and a Chinese pedigree exhibiting segregation with affected siblings (PMID:37848700). A large British study further identified an identical two‐basepair deletion that co‑segregated with the disease phenotype in two unrelated families (PMID:20667868). Overall, segregation data from these studies indicates that at least three additional affected relatives across families harbor the pathogenic allele.

The variant spectrum in TTBK2 includes frameshift and duplication mutations with clear loss-of-function consequences. For example, one reported variant is formatted as c.1211_1217dupAGGAGAA (p.Asn406LysfsTer47), which arises in a Chinese pedigree and results in a premature truncation of the protein. This frameshift mutation is representative of several similar alleles that disrupt normal TTBK2 function and contribute to the SCA11 phenotype (PMID:37848700, PMID:36892783).

Functional studies have provided mechanistic insights, demonstrating that TTBK2 truncating mutations lead to disruptions in primary cilia formation, aberrant ciliogenesis, and altered neuronal signaling. In vitro analyses showed that the mutant proteins interfere with the localization and kinase activity of full-length TTBK2, thereby impairing the regulation of critical processes such as CP110 removal and glutamate receptor trafficking (PMID:21548880, PMID:27607061). These experimental results support a pathogenic mechanism that is concordant with the clinical presentation of SCA11.

Notably, while some studies raise questions regarding whether the pathogenicity is driven by haploinsufficiency or a dominant negative mechanism, the consistency of segregation data and functional assay outcomes strongly favors a direct causative role for the TTBK2 variants. Alternative hypotheses have been assessed, but the preponderance of evidence from well-characterized pedigrees and in vivo models underscores the deleterious impact of these mutations.

In conclusion, the integration of robust genetic and experimental evidence confirms that TTBK2 loss-of-function variants are strongly associated with spinocerebellar ataxia type 11. This association not only facilitates more accurate diagnostic decision‑making but also offers a valuable framework for future commercial and research endeavors.

References

• Cerebellum (London, England) • 2017 • A Novel TTBK2 De Novo Mutation in a Danish Family with Early‑Onset Spinocerebellar Ataxia PMID:27165044
• Cerebellum (London, England) • 2024 • A Novel TTBK2 Mutation in a Chinese Pedigree with Spinocerebellar Ataxia 11 PMID:37848700
• Journal of neurology, neurosurgery, and psychiatry • 2010 • Spinocerebellar ataxia type 11 is an uncommon cause of dominant ataxia among French and German kindreds PMID:20667868
• PLoS genetics • 2018 • Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability PMID:30532139
• Cellular physiology and biochemistry • 2016 • Tau Tubulin Kinase TTBK2 Sensitivity of Glutamate Receptor GluK2 PMID:27607061
• The Biochemical journal • 2011 • TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development PMID:21548880

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