Journal of advanced research · 2026
TCF4 intronic CAG repeat length modulates the effect of ATXN3 on age at onset in spinocerebellar ataxia type 3.
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Wan Na, Wu Qi, Wan Linlin, Jiang Qian, Peng Linliu, Wang Chunrong, Lei Lijing, Long Zhe, He Lang, Shi Yuting, Qiu Rong, Tang Beisha, Chen Zhao, Jiang Hong
Аннотация
INTRODUCTION: Spinocerebellar ataxia type 3 (SCA3) is caused by ATXN3 CAG expansions, yet repeat length explains only 50-70% of age at onset (AO) variability, suggesting the influence of additional genetic modifiers. We investigated whether transcription factor 4 (TCF4), harboring an intronic CAG repeat and highly expressed in SCA3-vulnerable regions, modifies AO.
OBJECTIVES: To explore the modifying effect of TCF4 intronic CAG repeats on SCA3 AO and investigate the underlying molecular mechanisms.
METHODS: We conducted a cross-sectional study of 1,439 genetically confirmed Chinese SCA3 individuals (1,212 symptomatic, 227 asymptomatic). TCF4 CAG repeats were categorized as Short (7-13), Medium (14-39), and Long (≥40). Statistical frameworks included hierarchical regression, survival analyses, and extensive sensitivity testing. Functional validation was performed in HEK293T cells stably expressing normal (20Q) or pathogenic (84Q) ataxin-3, transfected with CDS-only or intron-retaining TCF4 constructs harboring 11, 24, or 100 intronic CTG repeats.
RESULTS: TCF4 showed no direct effect on AO but significantly modulated the ATXN3-AO relationship. Regression analyses revealed length-dependent amplification of the ATXN3 effect across TCF4 groups (-2.04 to -3.18 years/repeat). Modification was most pronounced in early-onset patients (AO ≤ 25; Δadjusted R2 = 0.048, p < 0.001). Survival analyses and extensive sensitivity tests consistently confirmed these findings. Mechanistically, TCF4 and ataxin-3 exhibited direct physical interaction. Notably, we identified a bidirectional pathogenic synergy: expanded ataxin-3 synergistically exacerbated TCF4 CTG length-dependent splicing defects, protein reduction, and RNA foci formation, while TCF4 expansion reciprocally promoted mutant ataxin-3 aggregation.
CONCLUSION: TCF4 intronic CAG repeat length-dependently modifies SCA3 age at onset through bidirectional molecular synergy with expanded ataxin-3. These findings reveal a novel intronic genetic modifier and establish the pathogenic interaction between non-coding and coding repeat expansion loci as a disease-modifying mechanism in repeat expansion disorders.
OBJECTIVES: To explore the modifying effect of TCF4 intronic CAG repeats on SCA3 AO and investigate the underlying molecular mechanisms.
METHODS: We conducted a cross-sectional study of 1,439 genetically confirmed Chinese SCA3 individuals (1,212 symptomatic, 227 asymptomatic). TCF4 CAG repeats were categorized as Short (7-13), Medium (14-39), and Long (≥40). Statistical frameworks included hierarchical regression, survival analyses, and extensive sensitivity testing. Functional validation was performed in HEK293T cells stably expressing normal (20Q) or pathogenic (84Q) ataxin-3, transfected with CDS-only or intron-retaining TCF4 constructs harboring 11, 24, or 100 intronic CTG repeats.
RESULTS: TCF4 showed no direct effect on AO but significantly modulated the ATXN3-AO relationship. Regression analyses revealed length-dependent amplification of the ATXN3 effect across TCF4 groups (-2.04 to -3.18 years/repeat). Modification was most pronounced in early-onset patients (AO ≤ 25; Δadjusted R2 = 0.048, p < 0.001). Survival analyses and extensive sensitivity tests consistently confirmed these findings. Mechanistically, TCF4 and ataxin-3 exhibited direct physical interaction. Notably, we identified a bidirectional pathogenic synergy: expanded ataxin-3 synergistically exacerbated TCF4 CTG length-dependent splicing defects, protein reduction, and RNA foci formation, while TCF4 expansion reciprocally promoted mutant ataxin-3 aggregation.
CONCLUSION: TCF4 intronic CAG repeat length-dependently modifies SCA3 age at onset through bidirectional molecular synergy with expanded ataxin-3. These findings reveal a novel intronic genetic modifier and establish the pathogenic interaction between non-coding and coding repeat expansion loci as a disease-modifying mechanism in repeat expansion disorders.