ArticleMolecular endocrinology (Baltimore, Md.)2008
Defective protein folding and intracellular retention of thyroglobulin-R19K mutant as a cause of human congenital goiter.
Article in Molecular endocrinology (Baltimore, Md.), 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
20 citing papers in PubMed, 41 citations in OpenAlex.
- Thyroidal expression of ER molecular chaperone GRP170 is required for efficient TSH-mediated thyroid hormone synthesis.JCI insight · 2025Article
- Perturbation of endoplasmic reticulum proteostasis triggers tissue injury in the thyroid gland.JCI insight · 2023Article
- The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases.Metabolites · 2022Review
- Article
- Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.Cold Spring Harbor perspectives in biology · 2019Review
- Loss-of-function PCSK9 mutants evade the unfolded protein response sensor GRP78 and fail to induce endoplasmic reticulum stress when retained.The Journal of biological chemistry · 2018Article
- Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology.Endocrine reviews · 2016Review
- Article
- Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis.The Journal of clinical endocrinology and metabolism · 2015Article
- Photoactivation-induced instability of rhodopsin mutants T4K and T17M in rod outer segments underlies retinal degeneration in X. laevis transgenic models of retinitis pigmentosa.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Congenital hypothyroidism caused by a novel homozygous mutation in the thyroglobulin gene.European journal of pediatrics · 2013Article
- GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum.Biochimica et biophysica acta · 2012Review
- Maturation of thyroglobulin protein region I.The Journal of biological chemistry · 2011Article
- Proteostasis strategies for restoring alpha1-antitrypsin deficiency.Proceedings of the American Thoracic Society · 2010Review
- From Split to Sibenik: the tortuous pathway in the cholinesterase field.Chemico-biological interactions · 2010Article
- New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.The Journal of clinical endocrinology and metabolism · 2010Article
- Calnexin improves the folding efficiency of mutant rhodopsin in the presence of pharmacological chaperone 11-cis-retinal.The Journal of biological chemistry · 2009Article
- The proteostasis boundary in misfolding diseases of membrane traffic.FEBS letters · 2009Review
- The cholinesterase-like domain, essential in thyroglobulin trafficking for thyroid hormone synthesis, is required for protein dimerization.The Journal of biological chemistry · 2009Article
- The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone.The Journal of clinical investigation · 2008Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.