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 oligodendrocytes 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 exon 10-intron 10 junction, c.1255 + 2T > C, which was segregated in affected patients with a pedigree of intellectual disability and epilepsy. To clarify an etiology of the novel variant, we generated a mouse model, Tenm4 ^ΔE10 , precisely mimicking the variant. 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 mouse. Minigene assay confirmed the variant caused an in-frame skipping of exon 10 (ΔE10), which the Tenm4 ^ΔE10 mouse certainly replicated. Homozygous Tenm4 ^ΔE10/ΔE10 mice exhibited significantly increased susceptibility to pentylenetetrazole-induced seizures. Their brain exhibited smaller corpus callosum than wildtype, and culture experiments showed impaired oligodendrocyte differentiation. Remarkably, ΔE10 transcript was natural alternative splicing present even in wildtype cells. During oligodendrocyte progenitor cells differentiation into oligodendrocytes, total Tenm4 transcripts drastically increased and proportion of full-length to ΔE10 transcripts was probably maintained. An imbalance in the proportion can impair oligodendrocyte development, causing the structural brain abnormalities and seizure susceptibility. In conclusion, our findings successfully elucidated a novel pathomechanism which emphasised the role of transcript isoform imbalance in neurodevelopmental diseases, and expanded a pleiotropic condition of TENM4 .