Naturally Occurring Mutations in the Thyroglobulin Gene

Abstract

Thyroglobulin (Tg) is a large glycoprotein dimer secreted into the follicular lumen. It serves as the matrix for the synthesis of thyroxine (T4) and triiodothyronine (T3), and the storage of thyroid hormone and iodide. In response to demand for thyroid hormone secretion, Tg is internalized into the follicular cell and digested in lysosomes. Subsequently, the thyronines T4 (approximately 80%) and T3 (approximately 20%) are released into the blood stream. Biallelic mutations in the Tg gene have been identified in several animal species and human patients presenting with goiter and overt or compensated hypothyroidism. In untreated patients, goiters are often remarkably large and display continuous growth. In most instances, the affected individuals have related parents and are homozygous for inactivating mutations in the Tg gene. More rarely, compound heterozygous mutations lead to a loss of function of both alleles. Molecular analyses indicate that at least some of these alterations result in a secretory defect and an endoplasmic reticulum storage disease (ERSD). This review discusses the nature and consequences of naturally occurring Tg gene mutations in humans and several animal species. Recent recommendations for the nomenclature of mutations have led to different numbering systems, an aspect that is discussed in order to clarify discrepancies between different publications.

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

“…As best as is currently known, all of the congenital hypothyroidism-inducing Tg mutants are defective for intracellular transport (26). A homozygous G2300R mutation (equivalent to residue 2,298 of mouse Tg) in the ChEL domain is responsible for congenital hypothyroidism in rdw rats (27,28), whereas we identified the Tg-L2263P point mutation as the cause of hypothyroidism in the cog mouse (29).…”

“…Both defective intramolecular chaperone function (14) and defective Tg dimerization (31) are expected consequences of such mutations. Additionally, it seems likely that many mutations in Tg regions I-II-III may fail to provide adequate homodimer stability, which could account for why many if not all cases of hypothyroidism with mutant Tg derive from a failure of intracellular transport through the secretory pathway (26).…”

Etiology of congenital hypothyroidism using thyroglobulin and ultrasound combination

“…If serum thyroglobulin was ology of thyroglobulin deficiency [30][31][32]. In such cases, scintigraphy and PCIV are redundant.…”

Maturation of Thyroglobulin Protein Region I

“…In general, Tg mutants causing genetic hypothyroidism and/or goiter are defective for secretion and thus fail to be delivered to the site of iodination (8). Rate-limiting in the overall process of intracellular transport is Tg export from the endoplasmic reticulum (ER) (9), which in turn is dependent on folding of the newly synthesized Tg protein (10 -13).…”