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The Effect of TRPML1 Mutations on Zinc and Calcium Permeability in MLIV

TRPML1 is an ion channel located on the membrane of late endosomes and lysosomes. It regulates calcium and zinc from the lumen to the cytosol. Loss-of-function mutations of TRPML1 lead to the lysosomal storage disease mucolipidosis type IV (MLIV), which affects 1 in 40,000 individuals. Approximately 95 percent of the individuals with this disease have a severe phenotype, which includes progressive retinal degeneration, psychomotor impairment, and moderate to severe intellectual disability. Patient mutations were replicated using site-directed mutagenesis to generate 10 mutations in TRPML1. Each mutation was proposed to alter TRPML1’s permeability of zinc and calcium. The intended goal of this research was to determine if altered permeability of zinc or calcium caused by each mutation corresponded to the severity of MLIV patients with that specific mutation. This research is expected to make a significant impact on the research contributing to MLIV and give insight into mechanisms behind the disease itself.

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