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

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Central hypothyroidism is a rare disorder characterized by insufficient thyroid hormone production due to inadequate TSH stimulation.
• The thyrotropin-beta (TSH-beta) subunit is essential for TSH bioactivity and proper thyroid hormone regulation.
• Genetic mutations can lead to dysfunctional hormones, impacting endocrine signaling pathways.

Purpose of the Study:

• To investigate the functional consequences of a specific TSH-beta subunit mutation (C105V) identified in families with central hypothyroidism.
• To elucidate the role of the carboxy-terminal cysteine residue in TSH structure and bioactivity.
• To confirm the in vivo and in vitro biological inactivity of the mutant TSH.

Main Methods:

• Genetic analysis of affected individuals from two related families to identify mutations in the TSH-beta subunit gene.
• Biochemical and physiological assessments of thyroid hormone levels and radioactive iodine uptake in patients.
• In vitro bioassays using recombinant TSH to evaluate the biological activity of the mutant protein.
• Comparison of TSH-stimulated thyroid hormone production between affected patients and unaffected siblings.

Main Results:

• A C105V mutation in the TSH-beta subunit gene was identified in individuals with central hypothyroidism.
• Affected patients exhibited low thyroid hormone levels despite measurable serum TSH, indicating impaired TSH action.
• The mutant TSH was biologically inactive in vitro and failed to stimulate thyroid hormone production in vivo.
• Structural analysis suggests the mutation disrupts a critical disulfide bond ('seat belt') necessary for TSH conformation and bioactivity.

Conclusions:

• The C105V mutation in the TSH-beta subunit results in biologically inactive TSH, causing central hypothyroidism.
• This finding underscores the critical importance of the TSH-beta subunit's carboxy-terminal region and the 'seat belt' structure for TSH function.
• The study provides insights into the molecular mechanisms underlying TSH action and the pathogenesis of central hypothyroidism.