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

TENM4 is a transmembrane protein belonging to the teneurin family. It is localized in neurons and oligodendrocytes, where it regulates oligodendrocyte maturation and myelination. While missense variants of TENM4 were reported to cause essential tremor and schizophrenia, we identified a novel variant of uncertain significance at the exon 10-intron 10 junction, c.1255+2T>C, which was segregated in affected patients with a pedigree of intellectual disability and epilepsy. Minigene assay confirmed that the variant caused an in-frame skipping of exon 10 (ΔE10). To clarify the etiology of the novel variant, we generated a mouse model, Tenm4^ΔE10, which replicated the exon 10-skipping. We evaluated the pathogenicity of the variant in multiple aspects by assessing Tenm4 transcripts, seizure susceptibility, brain pathology, and oligodendrocyte differentiation of the Tenm4^ΔE10 mice. Homozygous Tenm4^ΔE10/ΔE10 mice exhibited significantly increased susceptibility to pentylenetetrazole-induced seizures. Their brains exhibited a smaller corpus callosum compared to the wildtype, and culture experiments showed impaired oligodendrocyte differentiation. Remarkably, the ΔE10 transcript exhibited natural alternative splicing, even in wildtype cells. During the differentiation of oligodendrocyte progenitor cells into oligodendrocytes, total Tenm4 transcripts increased drastically, and the proportion of full-length to ΔE10 transcripts was likely maintained. An imbalance in the proportion can impair oligodendrocyte development, causing structural brain abnormalities and seizure susceptibility. In conclusion, our findings successfully elucidated a novel pathomechanism that emphasized the role of transcript isoform imbalance in neurodevelopmental diseases and expanded the pleiotropic condition of TENM4.