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

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 (Tenm4^ΔE10).

Main Methods:

• Minigene assay to confirm exon 10 skipping.
• Generation and analysis of the Tenm4^ΔE10 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 Tenm4^ΔE10/ΔE10 mice showed increased seizure susceptibility and smaller corpus callosum.
• Impaired oligodendrocyte differentiation was observed in Tenm4^ΔE10 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.