A New Silent Germline Mutation of the TSH Receptor: Coexpression in a Hyperthyroid Family Member with a Second Activating Somatic Mutation

Abstract

N372T is unlikely to cause altered thyroid function. This is consistent with the finding that only the index patient with the additional somatic mutation S281N was hyperthyroid.

Cases of BorderlineIn VitroConstitutive Thyrotropin Receptor Activity: How to Decide Whether a Thyrotropin Receptor Mutation Is Constitutively Active or Not?

“…Functional characterization via LRA indicates that, in spite of a 1.7-fold elevation of its basal cAMP, N372T is not constitutively active (19). This is consistent with the finding that only the apparent index patient with the additional and well-characterized constitutively active somatic mutation S281N (11)(12)(13)(14) showed hyperthyroidism (19).…”

“…We recently reported a large family with the new TSHR germline mutation N372T (19). Functional characterization via LRA indicates that, in spite of a 1.7-fold elevation of its basal cAMP, N372T is not constitutively active (19).…”

“…Functional characterization via LRA indicates that, in spite of a 1.7-fold elevation of its basal cAMP, N372T is not constitutively active (19). This is consistent with the finding that only the apparent index patient with the additional and well-characterized constitutively active somatic mutation S281N (11)(12)(13)(14) showed hyperthyroidism (19). These findings prompted us to re-examine previously described constitutively active TSHR mutations with a similar low increase of the basal cAMP level (<2.5-fold) relative to the WT TSHR like N372T.…”

Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More ActiveIn VitroActivities than Familial Thyrotropin Receptor Mutations

“…The LRA of constitutive activity as a function of TSHR expression determined by 125 I-bTSH binding or FACS analysis compared with the wild-type TSHR was described as the most comprehensive way of characterizing the IVA of constitutively activating TSHR mutations (78,(80)(81)(82). Therefore, we analyzed the TSHR mutations' published LRAs by a systematic review of the literature.…”

“…Until now, 46 different point mutations and two different deletions in the TSHR in TTNs (http://innere .uniklinikum-leipzig.de/tsh, accession date July 15, 1999) (51-76) ( Table 1) have been described. Many of these TSHR mutations have been recently characterized for their IVA by linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125 I-bTSH binding or FACS analysis compared with the wild-type TSHR, which is currently the most comprehensive in-vitro activity characterization method for TSHR mutations (5,77,78). We, therefore, used these data to investigate possible LRA differences between exclusively somatic, exclusively familial, and shared sporadic and somatic TSHR mutations and to analyze the correlation of LRAs with clinical activity characteristics of hot thyroid nodules.…”