Two novel mutations in the sixth transmembrane segment of the thyrotropin receptor gene causing hyperfunctioning...

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Autonomously functioning thyroid nodules (AFTNs) are a common cause of hyperthyroidism.
• Activating mutations in the thyrotropin receptor (TSHR) gene are frequently identified in AFTNs, often located in the sixth transmembrane segment or third intracellular loop.
• These mutations lead to constitutive receptor activation and excessive thyroid hormone production.

Observation:

• This study investigated two patients with toxic multinodular goiter and identified two previously undocumented mutations in the TSHR gene.
• The mutations, Phe631Val and Iso630Met, were located in the sixth transmembrane segment of the TSHR.
• Analysis involved isolating genomic DNA, amplifying relevant gene regions, and employing single-strand conformation polymorphism (SSCP) and automatic DNA sequencing.

Findings:

• Two novel TSHR mutations, Phe631Val and Iso630Met, were identified in hyperfunctioning thyroid nodules.
• Functional studies using site-directed mutagenesis and transfection into COS-7 cells demonstrated that both mutant receptors exhibit increased basal cyclic adenosine monophosphate (cAMP) levels compared to the wild-type receptor.
• This enhanced constitutive activity confirms the role of these mutations in causing hyperfunctioning thyroid nodules.

Implications:

• These findings expand the known spectrum of TSHR mutations associated with autonomously functioning thyroid nodules.
• Understanding these novel mutations can improve diagnostic accuracy and genetic counseling for patients with hyperthyroidism.
• Further research into the specific mechanisms of TSHR activation by these mutations may reveal new therapeutic targets for hyperthyroidism.