Maturation-dependent splicing alterations constrain SYNGAP1 splice-switching therapy

Abstract

Haploinsufficiency in SYNGAP1 causes a severe neurodevelopmental syndrome. SYNGAP1 protein is mainly detected in neuronal synapses. However, SYNGAP1 RNA is more widely expressed and strongly regulated via alternative splicing: alternative 3' splice site (A3SS) inclusion leads to non-productive transcripts that are degraded through nonsense-mediated decay. Recently, splice-switching oligonucleotides (SSOs) that redirect SYNGAP1 splicing to increase SYNGAP1 protein levels were developed. However, we hypothesized that during neuronal maturation, non-productive splicing may decrease to enhance functional transcripts in mature neurons. This would reduce the abundance of the SSO target transcript, limiting the potential for SSO treatment to increase neuronal SYNGAP1 expression. Using neural differentiation of human induced pluripotent stem cells, we show that the A3SS transcript is abundant in neural progenitors, astrocytes, microglia and immature neurons, with minimal presence in mature neurons. These data imply that SSOs targeting A3SS might lack therapeutic efficacy to rescue the neuronal phenotypes associated with SYNGAP1 haploinsufficiency.

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BibTeX RIS

BibTeX

@misc{kamp2026maturationdependent,
  title = {{Maturation-dependent splicing alterations constrain SYNGAP1 splice-switching therapy}},
  author = {J. A. Kamp and K. A. Wijnant and N. Maas and D. Gülyurt and M. J. Rieder and M. A. Jolfaei and C. Gontan and S. A. Kushner and Y. Elgersma and L. E. Vissers and N. Nadif Kasri and F. M. De Vrij},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.26.745682},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.26.745682v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Maturation-dependent splicing alterations constrain SYNGAP1 splice-switching therapy
AU  - J. A. Kamp
AU  - K. A. Wijnant
AU  - N. Maas
AU  - D. Gülyurt
AU  - M. J. Rieder
AU  - M. A. Jolfaei
AU  - C. Gontan
AU  - S. A. Kushner
AU  - Y. Elgersma
AU  - L. E. Vissers
AU  - N. Nadif Kasri
AU  - F. M. De Vrij
PY  - 2026
DA  - 2026/08/26
PB  - bioRxiv
DO  - 10.64898/2026.08.26.745682
UR  - https://www.biorxiv.org/content/10.64898/2026.08.26.745682v1
AB  - Haploinsufficiency in SYNGAP1 causes a severe neurodevelopmental syndrome. SYNGAP1 protein is mainly detected in neuronal synapses. However, SYNGAP1 RNA is more widely expressed and strongly regulated via alternative splicing: alternative 3' splice site (A3SS) inclusion leads to non-productive transcripts that are degraded through nonsense-mediated decay. Recently, splice-switching oligonucleotides (SSOs) that redirect SYNGAP1 splicing to increase SYNGAP1 protein levels were developed. However, we hypothesized that during neuronal maturation, non-productive splicing may decrease to enhance functional transcripts in mature neurons. This would reduce the abundance of the SSO target transcript, limiting the potential for SSO treatment to increase neuronal SYNGAP1 expression. Using neural differentiation of human induced pluripotent stem cells, we show that the A3SS transcript is abundant in neural progenitors, astrocytes, microglia and immature neurons, with minimal presence in mature neurons. These data imply that SSOs targeting A3SS might lack therapeutic efficacy to rescue the neuronal phenotypes associated with SYNGAP1 haploinsufficiency.
ER  -

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