The ATXN2 9 bp duplication in SCA3: clarifying evidence and correcting misinterpretations.

Abstract

Lauerer et al. (Acta Neuropathol Commun 13:157, 2025) recently investigated the role of ATXN2 variants, including intermediate CAG repeats and a 9-bp duplication, in spinocerebellar ataxia type 3 (SCA3). While their study contributes valuable data, several of their interpretations diverge from our previous findings and require clarification. Our original hypothesis was not that the duplication alone modified age at onset, but that its effect emerges in combination with an intermediate-length ATXN2 allele (29 CAGs). Their claim of a protective effect is unsupported by non-significant results, which cannot establish equivalence. Furthermore, evidence from multiple studies demonstrates that both ATG1 and ATG2 can initiate translation, with redundancy explaining the in vivo ~ 140-145 kDa ATXN2 protein, thereby countering the assertion that the duplication is relevant only at the DNA level. We also correct the misattribution of our segregation analyses and emphasize that low frequency does not negate biological significance, as rare variants can act as genetic modifiers. Taken together, convergent DNA, RNA, and protein evidence supports the relevance of the ATXN2 9-bp duplication as part of the broader network of modifiers in SCA3.