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Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese
V Vanvooren1, S Uchino, L Duprez
1Institute of Interdisciplinary Research, University of Brussels, Campus Erasme, Route de Lennik 808, B-1070 Brussels, Belgium. vvvooren@ulb.ac.be
Objective:
Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs.
Design:
Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced.
Results:
In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found.
Conclusions:
If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.
Insights
Activating mutations in the thyrotropin receptor (TSHR) and G(alpha)s were investigated in Japanese autonomously functioning thyroid nodules (AFTNs). Four TSHR mutations and one G(alpha)s mutation were identified, suggesting their role in AFTN development.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Activating mutations in the thyrotropin receptor (TSHR) are common in European autonomously functioning thyroid nodules (AFTNs).
- The prevalence and role of these mutations in Japanese AFTNs remain less understood.
- Previous studies identified only one TSHR mutation in Japanese AFTNs.
Purpose of the Study:
- To determine the frequency of activating mutations in the TSHR and G(alpha)s genes in Japanese AFTNs.
- To compare mutation prevalence between Japanese and European AFTN patients.
- To investigate potential alternative genetic causes for AFTNs lacking TSHR/G(alpha)s mutations.
Main Methods:
- Genomic DNA was extracted from 10 Japanese AFTN tissue samples.
- The TSHR and G(alpha)s genes were amplified and sequenced.
- Sequence analysis identified specific mutations within these genes.
Main Results:
- Four distinct mutations were identified in the TSHR gene (T632A, I486M, M453T, L512R).
- One mutation (R201H) in the G(alpha)s gene was found in a sample negative for TSHR mutations.
- When considering solitary nodules, the mutation proportion (70%) matched that observed in European patients.
Conclusions:
- Activating mutations in TSHR and G(alpha)s contribute to the development of Japanese AFTNs.
- The findings support a similar genetic basis for AFTNs in Japanese and European populations, particularly in solitary nodules.
- Other genetic factors likely contribute to the pathogenesis of AFTNs in multinodular goiters.