TGM6 and Spinocerebellar Ataxia Type 35

The association between TGM6 and spinocerebellar ataxia type 35 is supported by several case reports and cohort studies, yet it remains controversial due to conflicting segregation data. A key case report documented an Italian patient with late‑onset, slowly progressive cerebellar ataxia, scanning speech, ocular dysmetria, and pyramidal tract signs who carried the heterozygous c.1024C>T (p.Arg342Trp) variant (PMID:33160304). This report, together with a multi‐patient study that identified TGM6 mutations in 109 probands (PMID:25253745), initially provided compelling genetic evidence for a pathogenic role for TGM6 in SCA35. In these studies, various missense and small structural variants were identified, with recurrent detection of variants such as c.1024C>T (p.Arg342Trp) and c.1550T>G (p.Leu517Trp) suggesting a mutational hotspot.

However, subsequent investigations have raised concerns over the specificity of TGM6 mutations, as certain variants (for example, p.Leu517Trp) did not segregate with disease in some pedigrees and were found at inflated frequencies in control populations (PMID:32426513, PMID:30670339, PMID:33588035). While functional assessment studies consistently report that TGM6 mutants exhibit reduced transamidase activity and instability—factors that could contribute to neuronal dysfunction (PMID:23206699, PMID:28934387)—the overall picture remains clouded by nonsegregation in some families and the possibility of low penetrance.

Taken together, the genetic evidence, despite implicating several recurrent TGM6 variants across multiple studies, is counterbalanced by significant conflicting findings. This leaves the overall gene‐disease association in a state of dispute. Additional rigorous segregation analyses and broader population screening are warranted to clarify the precise role of TGM6 variants in the pathogenesis of SCA35.

Key Take‑home: While TGM6 mutations have been linked to SCA35 through both genetic and functional studies, conflicting segregation and frequency data necessitate cautious clinical interpretation in diagnostic settings.

References

• BMC Neurology • 2020 • A case report of late‑onset cerebellar ataxia associated with a rare p.R342W TGM6 (SCA35) mutation PMID:33160304
• Neurology • 2014 • Spinocerebellar ataxia 35: novel mutations in TGM6 with clinical and genetic characterization PMID:25253745
• Neurology Genetics • 2020 • TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35 PMID:32426513
• Parkinsonism & Related Disorders • 2019 • A significant inflation in TGM6 genetic risk casts doubt in its causation in spinocerebellar ataxia type 35 PMID:30670339
• Gene • 2021 • TGM6 might not be a specific causative gene for spinocerebellar ataxia resulting from genetic analysis and functional study PMID:33588035
• Biochemical and Biophysical Research Communications • 2013 • Spinocerebellar ataxia type 35-associated transglutaminase 6 mutants sensitize cells to apoptosis PMID:23206699
• Human Molecular Genetics • 2017 • Mutations in TGM6 induce the unfolded protein response in SCA35 PMID:28934387

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