ATXN8OS Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 ( SCA48 / STUB1 )
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.
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BibTeX
@article{mouraux2026atxn8os,
title = {{ATXN8OS Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 ( SCA48 / STUB1 )}},
author = {Charlotte Mouraux and Jean‐loup Méreaux and Claire‐sophie Davoine and Léna Guillot Noel and Emilien Petit and Quentin Thomas and Adem Nasraoui and Anna Heinzmann and Claire Ewenczyk and Alexis Brice and Alexandra Durr and Giulia Coarelli},
journal = {Movement Disorders},
year = {2026},
month = sep,
doi = {10.1002/mds.70534},
url = {https://hal.science/hal-05803595v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - ATXN8OS Intermediate Expansion Acts as a Genetic Modifier in Spinocerebellar Ataxia Type 48 ( SCA48 / STUB1 )
AU - Charlotte Mouraux
AU - Jean‐loup Méreaux
AU - Claire‐sophie Davoine
AU - Léna Guillot Noel
AU - Emilien Petit
AU - Quentin Thomas
AU - Adem Nasraoui
AU - Anna Heinzmann
AU - Claire Ewenczyk
AU - Alexis Brice
AU - Alexandra Durr
AU - Giulia Coarelli
PY - 2026
DA - 2026/09/21
JO - Movement Disorders
DO - 10.1002/mds.70534
UR - https://hal.science/hal-05803595v1
AB - 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.
SN - 0885-3185
SN - 1531-8257
ER -