The FGF14-SCA27B GAA•TTC Repeat Shows a Marked Somatic Expansion Bias in the Cerebellum
David Pellerin1, Jean-Loup Méreaux2, Susana Boluda2, Matt Danzi1, Marie-Josee Dicaire3, Claire-Sophie Davoine2, David Genis4, Guinevere Spurdens1, Jillian Hammond5, Brandon Gerhart6, Mathilde Renaud7, Céline Bonnet7, Jill Napierala6, Ira Deveson5, Marek Napierala6, Alexis Brice2, Laura Molina Porcel8, Danielle Seilhean2, Stephan Zuchner9, Alexandra Durr2, Bernard Brais3
1University of Miami, 2Sorbonne Université, 3McGill University, 4Hospital Universitari de Girona Dr. Josep Trueta (ICS) & Hospital Santa Caterina IAS, 5Garvan Institute of Medical Research, 6University of Texas Southwestern Medical Center, 7Université de Lorraine, 8University of Barcelona, 9University of Miami School of Medicine
Objective:
To study the somatic instability profile 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 late-onset autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that the disease process is restricted to the cerebellum. Although the expanded repeat is highly unstable during intergenerational transmission, whether it exhibits somatic instability remains unknown.
Design/Methods:
We determined the GAA•TTC repeat length and expansion index, which measures the degree of somatic expansion, on 156 serial blood samples from 69 individuals, fibroblasts and iPSCs from three SCA27B patients, and post-mortem brain tissues from six controls and six SCA27B patients. We also performed methylation analysis of FGF14 in the post-mortem cerebellar hemisphere of four controls and four SCA27B patients using targeted long-read nanopore sequencing.
Results:
Blood samples exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. There was minimal difference in the length of the expanded GAA•TTC tract between blood samples, fibroblasts, and iPSCs. In the brain, the GAA•TTC repeat was remarkably stable across the 15 regions analyzed, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. The levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. Furthermore, we found no significant difference in methylation of FGF14, its promoters, or the region surrounding the repeat locus between patients and controls.
Conclusions:
Our study revealed that the FGF14 repeat exhibits a unique cerebellar-specific expansion bias, potentially accounting for the pure cerebellar involvement in SCA27B.
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