Non-Canonical Functions of a Mutant TSC2 Protein in Mitotic Division

Tuberous Sclerosis Complex (TSC) is a debilitating neurodevelopmental disorder characterized by a variety of clinical manifestations including epilepsy, autism, and intellectual disability. TSC is caused by mutations in the TSC1 or TSC2 genes, which encode the hamartin/tuberin proteins respectively. These proteins function as a heterodimer that negatively regulates mechanistic Target of Rapamycin Complex 1 (mTORC1). TSC research has focused on the effects of mTORC1, a critical signaling hub, on regulation of diverse cell processes including metabolism, cell growth, translation, and neurogenesis. However, non-canonical functions of TSC2 are not well studied, and the potential disease-relevant biological mechanisms are not well understood. We observed aberrant multipolar mitotic division, a novel phenotype, in TSC2 mutant iPSCs. The multipolar phenotype is not meaningfully affected by treatment with mTORC1 inhibition, suggesting that multipolar division is an mTORC1-independent phenotype. We further observed dominant negative activity of the mutant form of TSC2 in producing the multipolar division phenotype. These data expand the knowledge of TSC2 function and pathophysiology which will be highly relevant to future treatments for patients with TSC. Highlights Novel multipolar division in patient-derived iPSCs with mutant form of tuberin, TSC2 encoded protein Mutant tuberin may act in a dominant negative, mTORC1-independent manner eTOC Tuberous sclerosis complex (TSC) is a disorder caused by mutations in TSC1 or TSC2 genes leading to mTORC1 hyperactivity. Chalkley and colleagues found that a mutant microdeletion allele of TSC2 causes multipolar division in human induced pluripotent stem cells. Chalkley and colleagues also found that the multipolar division from mutant TSC2 may have a dominant negative mechanism and be mTOR1-independent.