ATXN8OS
Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 (
SCA48
/
STUB1
Charlotte Mouraux, Jean‐Loup Méreaux, Claire‐Sophie Davoine, Léna Guillot Noel, Emilien Petit, Quentin Thomas, Adem Nasraoui, Anna Heinzmann, Claire Ewenczyk, Alexis Brice, Alexandra Durr, Giulia Coarelli Abstract
Background
Association between monoallelic STUB1 variant and expanded ATXN8OS alleles was recently reported, suggesting a pathogenic interaction that may influence spinocerebellar ataxia type 48 (SCA48) phenotype.
Objectives
We investigated the frequency and clinical impact of ATXN8OS in a large cohort of STUB1 carriers compared to individuals with other ataxias and controls.
Methods
Ataxic individuals and controls from the SPATAX/BIOMOV cohorts (Paris Brain Institute) were screened for ATXN8OS and other CAG expansions using polymerase chain reaction (PCR)/repeat‐prime PCR (RP‐PCR) and ExpansionHunter . STUB1 carriers underwent whole‐genome or exome sequencing.
Results
Our cohort comprised 12 biallelic STUB1 carriers (SCAR16) and 67 monoallelic STUB1 carriers (SCA48) without other causative variants. ATXN8OS expansions (84–177 CTA/CTG repeats) were identified in seven SCA48 individuals (10.5%) who exhibited earlier onset (median age 28 vs. 47 years, P < 0.001) compared to other SCA48 individuals but with similar clinical presentation. ATXN8OS expansions were also found in two healthy controls older than 50 years (2/286, 0.7%) and in eight index cases with autosomal dominant ataxia (8/400, 2%), including four carrying another molecular diagnosis without any effect on the phenotype. Other intermediate expansions were identified in individuals with SCA48: seven (10.5%) carried intermediate TBP alleles (40–46 CAG/CAA) without any effect on dementia prevalence; four carried intermediate HTT alleles (28–29 CAG); and three carried intermediate ATXN1 expansions (38 CAG).
Conclusions
ATXN8OS intermediate expansion acts as a genetic modifier in SCA48 but not in other ataxias. Moreover, expanded intermediate alleles in neurodegenerative disease genes were present in one‐third of SCA48 individuals. These alleles may increase polyglutamine burden, potentially saturating STUB1 E3 ubiquitin ligase activity. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.