We have begun to explore the utility of C. elegans in modeling rare human genetic disorders of metabolism. In collaboration with Dr. Semple (Univ of Cambridge, UK), we have initiated a proof-of-principle study using the DAF-2 insulin-like receptor in the worm to model mutations in the human insulin receptor (INSR). Combining bioinformatic analysis and in vivo assays, we are testing mutations located throughout DAF-2 for phenotypic consequences and correlating those changes with human disease alleles. We have exploited the relatively quick and easy forward genetics, genome editing, and phenotypic assays of the C. elegans system to gain insight into human insulin receptor functional domains, including creating an allelic series of mutations in a single amino acid residue that mimics human disease severity. In collaboration with Drs. Marta Kostrouchova and Kostrouch (Charles University, Prague) we have identified a protein in C. elegans that is related to human perlipins, proteins that associate with lipid droplets and regulate their metabolism. No prelipin homolog had previously been identified in C. elegans, raising the possibility that fat droplet regulation and metabolism in the nematode was different. Our results suggest an evolutionarily conserved, perlipin-like protein family is regulating lipid droplets in metazoan.
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