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    Cases of Borderline in Vitro Constitutive Thyrotropin Receptor Activity: How to Decide Whether a Thyrotropin Receptor Mutation Is Constitutively Active or Not?
    (Mary Ann Liebert, Inc, 2009) Mueller, Sandra; Gözü, Hülya İliksu; Bircan, Rifat; Jaeschke, Holger; Eszlinger, Markus; Lueblinghoff, Julia; Paschke, Ralf
    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.
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    High Prevalence of TSHR/Gs alpha Mutation-negative Clonal Hot Thyroid Nodules (HNs) in a Turkish Cohort
    (Georg Thieme Verlag Kg, 2011) Sancak, Seda; Jaeschke, Holger; Eren, Funda; Özlem, T.; Güllüoğlu, Bahadır; Şen, L. S.; Eszlinger, Markus; Bircan, R.
    Whereas the majority of hot thyroid nodules are caused by somatic TSH-receptor mutations, the percentage of TSH-receptor mutation negative clonal hot nodules (HN) and thus the percentage of hot nodules likely caused by other somatic mutations are still debated. This is especially the case for toxic multinodular goiter (TMNG). 35 HNs [12 solitary hot nodules (SHN), 23 TMNG] were screened for somatic TSHR mutations in the exons 9 and 10 and for Gs alpha mutations in the exons 7 and 8 using DGGE. Determination of X-chromosome inactivation was used for clonality analysis. Overall TSHR mutations were detected in 14 out of 35 (40%) HNs. A nonrandom X-chromosome inactivation pattern was detected in 18 out of 25 (72%) HNs suggesting a clonal origin. Of 15 TSHR or Gs alpha mutation negative cases 13 (86.6%) showed nonrandom X-chromosome inactivation, indicating clonal origin. The frequency of activating TSHR and/or Gs alpha mutations was higher in SHNs (9 of 12) than in TMNGs (6 of 23). There was no significant difference for the incidence of clonality for HNs between TMNGs or SHNs (p: 0.6396). Activating TSHR and/or Gs alpha mutations were more frequent in SHNs than in TMNG. However, the frequency of clonality is similar for SHN and TMNG and there is no significant difference for the presence or absence of TSHR and/or Gs alpha mutations of clonal or polyclonal HNs. The high percentage of clonal mutation-negative HNs in SHN and TMNG suggests alternative molecular aberrations leading to the development of TSHR mutation negative nodules.
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    Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More Active in Vitro Activities than Familial Thyrotropin Receptor Mutations
    (Mary Ann Liebert, Inc, 2011) Lueblinghoff, Julia; Eszlinger, Markus; Jaeschke, Holger; Mueller, Sandra; Bircan, Rifat; Gözü, Hülya İliksu; Paschke, Ralf
    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.