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Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular
H P Holzapfel1, D Führer, P Wonerow
1Department of Internal Medicine III, University of Leipzig, Germany.
Abstract:
Constitutively activating mutations in the TSH receptor (TSHR) gene and in the Gs alpha gene are frequent molecular causes for solitary toxic nodules of the thyroid. However, the etiology of toxic multinodular goiter is still largely unknown. Therefore, DNA from nodular and quiescent surrounding tissue of six patients with toxic multinodular goiters was screened for mutations in exons 9 and 10 of the TSHR gene and exons 7-10 of the Gs alpha gene by direct automated sequencing. In one patient, two different somatic TSHR mutations were identified in two different toxic nodules (L632I and F631L). In another patient, two different toxic nodules harbored the same TSHR mutation (I630L), whereas only one TSHR mutation (F631L) was identified in one of the two toxic nodules of an additional patient. In the other three patients, no mutations could be found in exons 9 and 10 of the TSHR gene or in exons 7-10 of the Gs alpha gene. Our results demonstrate that not only solitary toxic adenomas but also toxic multinodular goiters can be caused by constitutively activating mutations of the TSHR. In addition to mutations in the TSHR and possibly in Gs alpha, there are probably other still unknown mechanisms that cause hot nodules in toxic multinodular goiters.
Insights
Constitutively activating mutations in the TSH receptor (TSHR) gene cause toxic multinodular goiters. Further research is needed to identify other molecular mechanisms involved in hot nodule formation.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Solitary toxic thyroid nodules are often caused by mutations in the TSH receptor (TSHR) or Gs alpha genes.
- The molecular basis of toxic multinodular goiter (TMG) remains largely unknown.
Purpose of the Study:
- To investigate the role of TSHR and Gs alpha gene mutations in the etiology of toxic multinodular goiter.
Main Methods:
- Direct automated sequencing of TSHR exons 9-10 and Gs alpha exons 7-10 in DNA from nodular and surrounding thyroid tissue of six TMG patients.
- Analysis of somatic mutations in toxic nodules.
Main Results:
- TSHR mutations were identified in toxic nodules of three out of six patients.
- One patient had two distinct TSHR mutations in separate nodules (L632I, F631L).
- Another patient had the same TSHR mutation (I630L) in two nodules; a third patient had one TSHR mutation (F631L) in one of two nodules.
Conclusions:
- Constitutively activating TSHR mutations are a cause of toxic multinodular goiters, similar to solitary toxic adenomas.
- Other unknown mechanisms likely contribute to the development of hot nodules in TMG, beyond TSHR and Gs alpha mutations.