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Transcript Imbalance from TENM4 Exon Skipping: Effects on Epilepsy and Genetic Pleiotropy.

Yasuyo Suzuki1, Daniela Tiaki Uehara2, Yasushi Enokido3

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Summary

A novel TENM4 gene variant causes exon 10 skipping, leading to oligodendrocyte dysfunction and increased seizure susceptibility in mice. This highlights transcript isoform imbalance in neurodevelopmental disorders.

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • TENM4 (teneurin-4) is a transmembrane protein crucial for oligodendrocyte maturation and myelination.
  • Known TENM4 variants are linked to essential tremor and schizophrenia.
  • A novel variant, c.1255+2T>C, at the exon 10-intron 10 junction was identified in patients with intellectual disability and epilepsy.

Purpose of the Study:

  • To investigate the pathogenicity of the novel TENM4 variant c.1255+2T>C.
  • To elucidate the role of TENM4 transcript isoform imbalance in neurodevelopmental disorders.
  • To characterize a mouse model with TENM4 exon 10 skipping (Tenm4ΔE10).

Main Methods:

  • Minigene assay to confirm exon 10 skipping.
  • Generation and analysis of the Tenm4ΔE10 mouse model.
  • Assessment of seizure susceptibility, brain pathology, and oligodendrocyte differentiation in mice.

Main Results:

  • The c.1255+2T>C variant induced in-frame skipping of exon 10 (ΔE10).
  • Homozygous Tenm4ΔE10/ΔE10 mice showed increased seizure susceptibility and smaller corpus callosum.
  • Impaired oligodendrocyte differentiation was observed in Tenm4ΔE10 mice and cell cultures.
  • The ΔE10 transcript is a naturally occurring alternative splice form, but its proportion is critical.

Conclusions:

  • Transcript isoform imbalance of TENM4, specifically the ratio of full-length to ΔE10, is a novel pathomechanism in neurodevelopmental diseases.
  • TENM4 exon 10 skipping contributes to intellectual disability and epilepsy phenotypes.
  • This study expands the understanding of TENM4's pleiotropic roles in the nervous system.