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Abstract

Glycoprotein M6a (GPM6A) is a tetraspan protein found within the neuronal and astrocytic membrane of the mammalian nervous system. GPM6A localizes to the leading edge of neuronal lamellipodia and promotes the polymerization of filamentous-actin (F-actin), greatly assisting in the development of immature neurites. A patient seen and genetically analysed at the BC Children’s Hospital Research Institute presenting with global developmental delay, hypotonia, facial dysmorphisms, and ASD was identified as harbouring a de novo heterozygous point mutation within GPM6A’s first transmembrane domain, replacing a tyrosine to serine (Y37S). Importantly, the molecular mechanisms inducing such phenotypes are still largely unknown. Utilizing CRISPR/Cas9 gene editing, GPM6A-Y37S hiPSC-derived neural progenitor cells, cortical neurons, and cerebral organoids have been established for the first time and characterized. Here we demonstrate the Y37S GPM6A point mutation reduces neurite outgrowth in a hiPSC-derived neuronal monolayer, alters glial development in hiPSC-derived cerebral organoids, and decreases GPM6A protein expression in all aforementioned models.