Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism

TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmune hyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 constitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis of FNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goiter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjects with sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations have been reported. The main characteristic of SNAH is a negative family history. Additional consequences of prolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis) have often been reported in SNAH. No genotype-phenotype relationship has been reported in patients with germline TSHR mutations. There is no association of in vitro activities determined by linear regression analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical course in patients with SNAH. However, additional genetic, constitutional or environmental factors are most likely responsible for the phenotypic variations of the disease and the lack of correlation between in vitro activities of the TSHR mutations and the severity of hyperthyroidism. (C) 2010 Elsevier Ireland Ltd. All rights reserved

Does the mitochondrial genome much more stabile in the aggressive papillary thyroid cancers ('PTCs)? - the preliminary findings

[No Abstract Available

Does the mitochondrial genome much more stabile in the aggressive papillary thyroid cancers ('PTCs)? - The preliminary findings

[No Abstract Available

Cases of Borderline in Vitro Constitutive Thyrotropin Receptor Activity: How to Decide Whether a Thyrotropin Receptor Mutation Is Constitutively Active or Not?

Background: Previous in vitro data for several constitutively activating thyrotropin receptor (TSHR) mutations reported divergent results for the constitutive activity of the same mutations. Moreover, several case reports have highlighted the difficulties in determining whether a TSHR mutation is constitutively active or not. Retrospectively, this has repeatedly been the case for mutants with only a slight increase of basal cAMP activity. We re-examined 10 previously described TSHR germline mutations with minor increases of basal cAMP activity and analyzed the influences of the cell line and vector system on the basal receptor activity. Methods: TSHR mutations were characterized by determination of cell surface expression, cAMP accumulation, and linear regression analysis of constitutive activity. Results: Re-examination of the previously described constitutively active TSHR germline mutations did not show constitutive activity for R310C and N670S as tested in COS-7 cells and confirmed constitutive activity for the other eight mutations. However, mutant N670S showed a slight but significant increase of basal activity measured by linear regression analysis when analyzed in HEKGT cells transiently transfected with pcDNA but not with the pSVL vector. This was not the case for R310C. Conclusions: Our findings indicate that current methods to precisely classify mutants with only a slight increase of the basal activity as constitutively active are limited. The results concerning the level of the basal activity can be influenced by the vector and/or the cell system. A comprehensive clinical characterization of the respective patients appears as a necessary and promising adjunct for the activity classification of these borderline mutations.Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [DFG/Pa 423/14-1]We thank Eileen Boesenberg and Saskia Fiedler (Department of Internal Medicine III, University of Leipzig, D-04103 Leipzig, Germany) for her excellent technical assistance and Micheline Misrahi (Laboratory of Molecular Genetics, Pharmacology and Hormones, University of Paris, France) and Susanne Neumann (Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, MD) for critical reading of the manuscript. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG/Pa 423/14-1)

Screening of the BRAF V600E mutation prevalance at papillary thyroid carcinomas (PTCs) in Turkish population

50th European-Society-of-Human-Genetics (ESHG) Conference -- MAY 27-30, 2017 -- Copenhagen, DENMARK[No Abstract Available]European Soc Human Gene

Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More Active in Vitro Activities than Familial Thyrotropin Receptor Mutations

Background: Germline thyrotropin receptor (TSHR) mutations are associated with sporadic congenital nonautoimmune hyperthyroidism and familial nonautoimmune hyperthyroidism. Somatic TSHR mutations are associated with toxic thyroid nodules (TTNs). The objective of the study was to define a relation of the clinical appearance and the in vitro activity (IVA) of the TSHR mutations described by several authors for these thyroid disorders. Methods: We analyzed the IVAs published as linear regression analysis (LRA) of the constitutive activity as a function of the TSHR expression and the basal cyclic adenosine monophosphate (cAMP) values to determine differences between exclusively somatic, exclusively familial, and shared sporadic and somatic TSHR-mutations. Further, we investigated correlations of the LRAs/basal cAMP values with clinical activity characteristics (CACs) of TTNs, such as largest diameter of the TTN and the age of the patient at thyroid surgery. Results: Shared sporadic and somatic mutations showed higher median LRA (14.5) and higher median basal cAMP values (fivefold) than exclusively familial mutations (6.1, p = 0.0002; 2.9-fold, p < 0.0001, respectively). Moreover, mutations shared between sporadic congenital nonautoimmune hyperthyroidism and toxic thyroid nodules (TTNs) showed higher median LRA/basal cAMP values (p < 0.0001) than exclusively somatic mutations in TTNs (5.1; 3.89-fold, respectively). Exclusively somatic mutations and exclusively familial mutations showed no significant difference in their median LRA values (p - 0.786) but a significant difference for basal cAMP values (p - 0.0006). The two examined CACs showed no correlation with the IVA characterized by LRA/basal cAMP values or with the presence or absence of a TSHR-mutation. Conclusions: This systematic analysis of published constitutively activating TSHR-mutations, their CACs, and their IVA provides evidence for higher IVA of shared sporadic and somatic TSHR mutations as compared with familial TSHR mutations. CACs of somatic TSHR mutations in TTNs did not have a clear association with the IVA as characterized by LRA or basal cAMP values.DFGGerman Research Foundation (DFG)European Commission [Pa 423/14-1, Pa 423/15-2, Ja 927/1-1]We thank H. Berger (Institute of Medical Statistics, University of Leipzig, Leipzig, Germany) for help with the statistical analysis. This research was funded by DFG grants Pa 423/14-1, Pa 423/15-2, and and Ja 927/1-1