ATXN8OS Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 (SCA48/ STUB1)

[en] 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.

Disciplines :

Neurology

Author, co-author :

Mouraux, Charlotte ; Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Méreaux, Jean‐Loup ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Davoine, Claire‐Sophie ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Noel, Léna Guillot ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Petit, Emilien ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Thomas, Quentin ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France ; Department of Neurology University Hospital of Dijon Dijon France

Nasraoui, Adem; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Heinzmann, Anna; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France ; Genetics Department, DMU Biogem Pitié‐Salpêtrière University Hospital Paris France

Ewenczyk, Claire; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France ; Genetics Department, DMU Biogem Pitié‐Salpêtrière University Hospital Paris France

Brice, Alexis ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Durr, Alexandra ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France

Coarelli, Giulia ; Sorbonne Université, Paris Brain Institute—ICM, Inserm, CNRS, APHP, Pitié‐Salpêtrière University Hospital Paris France ; Genetics Department, DMU Biogem Pitié‐Salpêtrière University Hospital Paris France

Language :

English

Title :

ATXN8OS Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 (SCA48/ STUB1)

Publication date :

21 September 2026

Journal title :

Movement Disorders

ISSN :

0885-3185

eISSN :

1531-8257

Publisher :

Wiley

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://movementdisorders.onlinelibrary.wiley.com/doi/pdf/10.1002/mds.70534

Available on ORBi :

since 22 September 2026

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