Category: Ataxia
Objective: To characterize somatic instability and molecular mechanisms of the FGF14 GAA•TTC repeat across serial blood samples, fibroblasts, induced pluripotent stem cells (iPSCs), and post-mortem brains.
Background: Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. The observed cerebellar-specific pathology and late onset of symptoms raise questions about somatic repeat instability and its molecular drivers.
Method: Somatic instability was evaluated by capillary electrophoresis of long-range PCR products across serial blood samples (156 samples from 69 individuals), fibroblasts, iPSCs, and post-mortem brain tissue from six SCA27B patients and six controls. To detect rare, ultra-large expansions, we performed small-pool PCR (SP-PCR) on post-mortem brain tissue from four SCA27B patients. FGF14 protein levels were measured by immunoblotting in post-mortem cerebellum specimens from four SCA27B patients and 14 controls, and methylation of FGF14 was assessed using long-read nanopore sequencing.
Results: Somatic instability was minimal in blood, fibroblasts, and iPSCs, even over decades. However, the cerebellar hemispheres and vermis displayed 3.15- and 2.72-fold higher levels of expansion compared to the other 13 brain regions studied. The levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. SP-PCR revealed ultra-large expansions (>1,000 triplets) in the cerebellum of a patient with a 432-GAA repeat, as measured in the blood. Protein levels in the cerebellum were 49.3% lower in SCA27B patients (p=0.07), consistent with a potential loss-of-function mechanism. Methylation of FGF14 (69.75 vs 68.95 5mC methylation frequencies, p=0.63), its promoters (2.00 vs 2.25, p=0.54 and 0.85 vs 0.80, p=0.63), or the region surrounding the repeat locus (82.37 vs 78.78, p=0.11) did not differ significantly between patients and controls.
Conclusion: Our study revealed that the FGF14 repeat exhibits a unique cerebellar-specific expansion bias, potentially accounting for the pure cerebellar involvement in SCA27B. Levels of FGF14 protein showed a trend towards reduction in SCA27B patients, consistent with a probable loss-of-function mechanism for the GAA•TTC repeat expansion.
To cite this abstract in AMA style:
D. Pellerin, JL. Méreaux, S. Boluda, MC. Danzi, MJ. Dicaire, CS. Davoine, P. Iruzubieta, B. Hayward, D. Genis, G. Spurdens, JM. Hammond, BJ. Gerhart, M. Renaud, C. Bonnet, JS. Napierala, IW. Deveson, M. Napierala, K. Usdin, A. Brice, LM. Porcel, D. Seilhean, SL. Zuchner, H. Houlden, A. Durr, B. Brais. The FGF14-SCA27B GAA•TTC Repeat Shows Marked Somatic Expansion in the Cerebellum [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/the-fgf14-sca27b-gaattc-repeat-shows-marked-somatic-expansion-in-the-cerebellum/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-fgf14-sca27b-gaattc-repeat-shows-marked-somatic-expansion-in-the-cerebellum/