This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, P. S. Articles by Arvan, P. Search for Related Content PubMed PubMed Citation Articles by Kim, P. S. Articles by Arvan, P.

Defective Protein Folding and Intracellular Retention of Thyroglobulin-R19K Mutant as a Cause of Human Congenital Goiter

Division of Endocrinology (P.S.K., S.M., B.L., S.A.H., J.-H.B.), University of Cincinnati, Cincinnati, Ohio 45267; Department of Biochemistry (P.J., B.P.), Faculty of Science, Mahidol University, Bangkok, Thailand; and Division of Metabolism, Endocrinology & Diabetes (J.L., P.A.), University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Prof. Peter Arvan, M.D., Ph.D., Chief, Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical Center, MSRB2 Room 5560, Ann Arbor, Michigan 48109. E-mail: parvan{at}umich.edu.

It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis.

This article has been cited by other articles:

				V. Pardo, J. Vono-Toniolo, I. G. S. Rubio, M. Knobel, R. F. Possato, H. M. Targovnik, P. Kopp, and G. Medeiros-Neto The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2938 - 2944. [Abstract] [Full Text] [PDF]

				J. Lee, X. Wang, B. Di Jeso, and P. Arvan The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization J. Biol. Chem., May 8, 2009; 284(19): 12752 - 12761. [Abstract] [Full Text] [PDF]