The molecular role of teneurin-3 in microphthalmia

Teneurins are synaptic adhesion receptor proteins that act as guidance cues for proper integration of neurons in the brain and the visual system. The Arg2563Trp missense mutation in the gene encoding teneurin-3 is associated with microphthalmia, a disease characterised by malformed eyes and mental impairments. Teneurin-3 is alternatively spliced at two sites, resulting in four isoforms. Previously, we reported that all these isoforms adopt completely different conformations, and two isoforms contain Arg2563Trp at intramolecular domain-domain contacts. On basis of molecular dynamics simulations, thermal stability, and cell clustering assays, we now show that specifically these two isoforms are stabilised on the molecular level, leading to loss of trans-cellualar adhesion. We aim to validate this using SAXS. Our findings would together provide unique insight into the molecular basis of microphthalmia, and the first example of isoform-specific pathogenicity from a point mutation.