Dominant Protein Interactions Influencing the Pathogenesis of Protein Misfolding Diseases of the Endocrine System

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 796-817-Diabetes Genetics & Epidemiology
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-817
Peter Arvan*1, Jordan Wright2, Leena Haataja2, Xiaofan Wang3, Jaemin Lee4, Ming Liu5 and Aaron Kellogg6
1Univ of Michigan Med Schl, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3Boston University, 4Children's Hospital Boston, Brookline, MA, 5University of Michigan Medical School, Ann Arbor, MI, 6University of Michigan
Misfolding of exportable proteins can trigger endocrinopathies, including Mutant INS-gene Induced Diabetes of Youth (autosomal dominant) and Congenital Hypothyroidism with deficient thyroglobulin (autosomal recessive).  Both proinsulin and thyroglobulin normally form homodimers; mutant versions of both proteins misfold in the endoplasmic reticulum (ER) triggering ER stress; and in both cases, heterozygosity creates potential for cross-dimerization between mutant and wild-type (wt) gene products.  Remarkably, we find in both cases, that whereas conditions favoring an increased stoichiometry of mutant gene product dominantly inhibits export of the wt partner, increased stoichiometry of the wt gene product actually rescues secretion of the mutant partner.  Unlike approaches involving the regulation of proteostasis networks, these dramatic effects appear protein-specific.  Surprisingly, the bi-directional consequences of secretory blockade and rescue occur simultaneously in the same cells.  Relative subunit expression level and stability — influencing the ratio of the assembly partners — appears to be a critical factor influencing which effect dominates the clinical phenotype.  We provide several in vivo correlates of these findings, obtained in animal models of disease.  Our results offer new insight into dominant versus recessive inheritance of conformational diseases, and offer opportunities for the development of new therapies.

Nothing to Disclose: PA, JW, LH, XW, JL, ML, AK

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH DK40344NIH DK48280
<< Previous Abstract | Next Abstract