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
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.
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.