A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene.

Abstract

Mutation of a critical carboxy-terminal cysteine residue (C105V) in the thyrotropin-␤ (TSH-␤ ) subunit gene was found in two related families with central hypothyroidism. Affected patients had low thyroid hormone levels and radioactive iodine uptake in the thyroid gland associated with measurable serum TSH. Thyrotropin-releasing hormonestimulated TSH secretion did not increase thyroid hormone production in these patients as compared to their unaffected siblings, suggesting that the mutant TSH was biologically inactive in vivo. Recombinant TSH harboring this mutation was confirmed to be biologically inactive in an in vitro bioassay. Based on crystallographic structure of chorionic gonadotropin, a disulfide bond between C19 and C105 in the TSH-␤ subunit is predicted to form the "buckle" of a "seat belt" that surrounds the common ␣ subunit and maintains the conformation and bioactivity of the hormone. This natural mutation of the TSH-␤ subunit confirms the importance of the seat belt in the family of pituitary and placental glycoprotein hormones. ( J. Clin. Invest. 1996. 97:1250-1256.)

The thyroid axis just got more complicated

“…Based on the finding of hypothyroidism in patients with TSH-β mutations -in whom thyrostimulin expression should be normal -Nakabayashi and colleagues suggest that peripherally produced thyrostimulin acts in a paracrine manner, with little effect on thyroid function (2). However, most of these patients have measurable, albeit low, concentrations of T 4 and T 3 in the serum (4)(5)(6)(7)(8), supporting the longstanding observation that primary forms of hypothyroidism may be clinically more severe than central forms. TSH-independent production and secretion of T 4 and T 3 from the thyroid have been attributed to constitutive activity of the unbound TSH receptor.…”

Expression of an in vitro biologically active equine LH/CG without C-terminal peptide (CTP) and/or beta26-110 disulphide bridge

“…More surprisingly, this result indicates that the fastening of the 26-110 bridge is not mandatory for the assembly of eLH/CG and eLH/CG which is required for the expression of its LH and FSH activities. By contrast, the disruption of this bond in hTSH abolished its bioactivity (Medeiros-Neto et al 1996).…”

Genetically Determined Central Hypothyroidism

“…Although that is usually the case, normal or mildly elevated TSH values can also be detected in certain cases, leading to an erroneous diagnosis of primary hypothyroidism. This phenomenon has been attributed to an aberrant TSH molecule, which is measurable by applied methodology but is biologically inactive [3][4][5]. Regardless of the mechanism involved one should be aware of this phenomenon in order to avoid misinterpretation and diagnose primary instead of secondary (central) hypothyroidism.…”