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Endocrine Abstracts (2006) 11 P824

ECE2006 Poster Presentations Thyroid (174 abstracts)

Clinical characterisation and genetic analysis of a large euthyroid family with TSH-receptor germline mutation (N372T) and a hyperthyroid index patient with an additional somatic tsh-receptor mutation (S281N) on the second TSH-receptor allele

Hulya Iliksu Gozu 1 , Rifat Bircan 2 , Knut Krohn 3 , Sandra Müller 4 , Dilek Yavuzer 5 , Gazenf Ekinci 6 , Haluk Sargin 7 , Mehmet Sargin 8 , Ekrem Orbay 9 , Beyazi Cirakoglu 10 & Ralf Paschke 11

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1Section of Endocrinology and Metabolism, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey; 2Department of Medical Biology, Marmara University Medical School, Istanbul, Turkey; 3Interdisciplinary Center of Clinical Research and 4Department of Internal Medicine III, University of Leipzig, Leipzig, Germany; 5Department of Pathology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey; 6Department of Radiology, Marmara University Medical Hospital, Istanbul, Turkey; 7Section of Endocrinology and Metabolism, 8Section of Endocrinology and Metabolism and 9Section of Endocrinology and Metabolism, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey; 10Department of Medical Biology, Marmara University Medical School, Istanbul, Turkey; 11Department of Internal Medicine III, University of Leipzig, Leipzig, Germany.


Objective: 21 different activating germline mutations have been identified up to date. We describe a large euthyroid family with a new TSH-receptor(TSHR) germline mutation where the hyperthyroid index patient also carries a somatic TSHR mutation.

Method: Mutation analysis of the exon 9 and 10 of the TSHR gene from the peripheral blood samples of the members of this family and toxic thyroid nodules of the index patient were performed by denaturing gradient gel electrophoresis in addition to direct sequencing. Local Ethical Committe approval has been obtained.

Results: We report a novel germline TSHR (N372T) mutation in blood sample of a 53 year-old man who presented with thyrotoxic storm. This mutation was also detected in six siblings and seven children of this patient. This mutation causes different phenotypic expression in this family ranging from normal thyroid to diffuse or nodular goiter with euthyroidism. Interestingly an additional somatic mutation (S281N) was also identified in the dominant toxic thyroid nodules of the index patient in the allele of the TSHR not affected by the germline mutation.

For both the single mutants N372T and S281N and the mixture of the two mutants N372T/S281N, basal cAMP level was higher in cells expressing the mutated receptors than in cells transfected with wild-type construct. Specific constitutive activity of the somatic mutation (S281N) was higher than the double mutant (N372T/S281N) and it was lowest in the germline mutant TSHR (N372T).

Conclusion: This family presents a new TSHR germline mutation located in the extracellular domain. The most likely explanations for euthyroidism are either the iodine deficiency or an unknown functional specificity of this mutation, since previously reported TSHR germline mutations with a similar low constitutive activity did cause hyperthyroidism. The only patient with hyperthyroidism in this family presented the first hot nodule with compound heterozygosity for two constitutively activating TSHR mutations

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
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