SynTEF1 restores the functional disease phenotype of SCA27B in an hiPSC-derived neuronal model
Gsell, F. G.; Pellerin, D.; Vinogradov, O.; Zuchner, S.; Haag, C.; Hedrich, U.; Napierala, M.; Saporta, M.; Yanick, C.; Brais, B.; Baumgartner, M. E.; Lerche, H.; Schwarz, N.; Synofzik, M. · neuroscience · 2026-09-06 · 原文
DOI：10.64898/2025.12.24.696231作者：14 位
Spinocerebellar Ataxia 27B (SCA27B), caused by a deep-intronic GAA repeat expansion in the first intron of the FGF14 gene, is one of the most frequent genetic ataxias. Its underlying disease mechanisms remain largely unknown, and disease-modifying therapies targeting upstream processes are lacking. Here we hypothesized that (i) SCA27B is driven by transcriptional repression of FGF14, which encodes a protein regulating ion channels at the axon initial segment (AIS), resulting in reduced Na+ channel availability and neuronal excitability, and that (ii) these defects can be restored by a synthetic elongation transcription factor (Syn-TEF1). We assessed FGF14 mRNA levels by qPCR and neuronal function by whole-cell patch-clamp recordings in iPSC-derived neurons from two SCA27B patients and two healthy controls. Patients carried GAA repeat expansions that were either monoallelic (391/16 repeats) or biallelic (315/290 repeats), exceeding the common pathogenicity threshold of >250 repeats. FGF14 mRNA levels were reduced approximately to 60% and 70% of control levels in monoallelic and biallelic SCA27B neurons, respectively. This was accompanied by impaired excitability, with cumulative act
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1. 人话版
Spinocerebellar Ataxia 27B (SCA27B), caused by a deep-intronic GAA repeat expansion in the first intron of the FGF14 gene, is one of the most frequent genetic ataxias.
Its underlying disease mechanisms remain largely unknown, and disease-modifying therapies targeting upstream processes are lacking.
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4. 证据与数字
Here we hypothesized that (i) SCA27B is driven by transcriptional repression of FGF14, which encodes a protein regulating ion channels at the axon initial segment (AIS), resulting in reduced Na+ channel availability and neuronal excitability, and that (ii) these defects can be restored by a synthetic elongation transcription factor (Syn-TEF1).
We assessed FGF14 mRNA levels by qPCR and neuronal function by whole-cell patch-clamp recordings in iPSC-derived neurons from two SCA27B patients and two healthy controls.
Patients carried GAA repeat expansions that were either monoallelic (391/16 repeats) or biallelic (315/290 repeats), exceeding the common pathogenicity threshold of >250 repeats.
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