Modeling Evolutionary Conserved Human Insulin Receptor Mutations in the Worm

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NIDDK	DIR-4

* FARE Award Winner

Authors

• D Bulger
• T Fukushige
• R Semple
• J Hanover
• M Krause

Abstract

Unlike common multi-factorial diseases, the etiology of rare monogenic disorders of severe insulin resistance can be traced to non-synonymous single nucleotide polymorphisms (nsSNPs), often affecting insulin signaling components. The insulin signaling pathway is evolutionarily conserved, althought the degree of conservation varies among the many proteins of this signaling cascade. The insulin receptor, designated INSR in humans and DAF-2 in the nematode C. elegans, is one component that is evolutionarily conserved and often mutated in patients with insulin resistance. We have modeled deleterious nsSNPs in human INSR in the homologous domains of C. elegans DAF-2 to define the nature and severity of impact on insulin signaling. In C. elegans, deleterious mutations manifest as dauer larva formation, increased longevity, and increased resistance to many forms of stress. In humans, deleterious mutations result in disorders of severe insulin resistance: type A insulin resistance, Rabson-Mendenhall syndrome, and Donohue syndrome. In this study, evolutionary conservation of nsSNPs was found to be associated with loss-of-function in both DAF-2 and INSR. Therefore, DAF-2 can be used to model and gain insights into human INSR disorders.

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