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Updated: Aug 8, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with
Katsuhiko Tsunekawa1, Kazumichi Onigata, Tadashi Morimura
1Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan.
Objective:
We identified and analyzed novel thyrotropin (TSH) receptor mutations in three Japanese families with resistance to TSH.
Design:
The TSH receptor gene was sequenced and the mutations were determined. The mutant TSH receptors were transfected into COS-7 cells, and their functions were analyzed.
Patients:
The patients were compound-heterozygotes for the R450H mutation and novel mutations in the TSH receptor gene. The first patient was a compound-heterozygote for R450H and V473I. The second sibling possessed R450H and R519C. The third sibling had R450H and R519G.
Results:
The R450H mutant exhibited moderately impaired receptor functions and a moderately decreased cell surface expression in agreement with previous results. The V473I mutant exhibited an almost normal TSH binding, a slightly decreased cyclic adenosine monophosphate (cAMP) response, a moderately decreased inositolphosphate (IP) response, and an almost normal cell surface expression. TSH binding and TSH stimulation of cAMP and IPs were markedly decreased in the R519C and R519G mutants. Cell surface expression was decreased in the R519C mutant and negligible in the R519G mutant. All of these mutants showed normal intracellular synthesis of TSH receptors.
Conclusions:
These novel inactivating mutations contribute to understanding of the structure-function relationship of the TSH receptor. To date, all of the patients with TSH resistance resulting from TSH receptor mutations identified in Japan possessed the R450H mutation at least in one allele. These observations suggest that the R450H mutation is a commonly observed TSH receptor mutation in patients with TSH resistance in Japan.
Insights
Novel thyrotropin (TSH) receptor mutations were identified in Japanese families with TSH resistance. The R450H mutation is common in Japanese patients with TSH resistance.
Area of Science:
- Endocrinology
- Molecular Genetics
- Receptor Biology
Background:
- Thyrotropin (TSH) resistance is a rare genetic disorder affecting thyroid hormone regulation.
- Mutations in the TSH receptor gene are a known cause of TSH resistance.
Purpose of the Study:
- To identify and characterize novel mutations in the TSH receptor gene in Japanese families with TSH resistance.
- To elucidate the structure-function relationship of the TSH receptor.
Main Methods:
- Sequencing of the TSH receptor gene to identify mutations.
- Transfection of mutant TSH receptors into COS-7 cells for functional analysis.
- Assessment of TSH binding, cyclic adenosine monophosphate (cAMP) and inositolphosphate (IP) responses, and cell surface expression of mutant receptors.
Main Results:
- Three novel inactivating mutations (V473I, R519C, R519G) were identified in addition to the known R450H mutation.
- Mutant receptors showed varying degrees of impaired TSH binding, signal transduction (cAMP and IP responses), and cell surface expression.
- The R450H mutation was present in all analyzed patients, suggesting its prevalence in Japanese TSH resistance cases.
Conclusions:
- Novel inactivating TSH receptor mutations expand the understanding of TSH resistance.
- The R450H mutation is a frequent genetic cause of TSH resistance in the Japanese population.
- These findings aid in the diagnosis and genetic counseling of patients with TSH resistance.
