TY  - JOUR
ID  - publicatio27342
TI  - Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling
SP  - E1039
EP  - E1045
A1  -  Lábadi Árpád
A1  -  Grassi Elisa Stellaria
A1  -  Gellén Balázs
A1  -  Kleinau Gunnar
A1  -  Biebermann Heike
A1  -  Ruzsa Beáta
A1  -  Gelmin Giulia
A1  -  Rideg Orsolya
A1  -  Miseta Attila János
A1  -  Kovács L. Gábor
A1  -  Patócs Attila Balázs
A1  -  Felszeghy Enik?
A1  -  Nagy Endre
A1  -  Mez?si Emese
A1  -  Persani Luca
SN  - 0021-972X
UR  - https://doi.org/10.1210/jc.2014-4511
VL  - 100
Y1  - 2015///
AV  - restricted
JF  - JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
IS  - 7
N2  - Context Congenital hypothyroidism (CH) is one of the most common inborn endocrine disorders with genetic background. Despite the well-established newborn CH screening program in Hungary, no systematic examination of the underlying genetic alterations has been performed yet. Objective We aimed to explore thyrotropin receptor (TSHR) mutations in a cohort of Hungarian patients with CH. Patients 85 unrelated patients with permanent primary CH, all diagnosed at newborn screening, were selected. Main outcome measures Coding exons of the TSHR gene were sequenced and evaluated together with the thyroid-specific clinical parameters. Functional features of the novel mutations were experimentally examined, and their comparative molecular models were built. Results In 4 patients (one heterozygous and three compound heterozygous) 7 TSHR mutations were identified. Among these N4321.50D and P4492.39L are novel missense alterations. Importantly, the N4321.50 residue is highly conserved among G protein-coupled receptors (GPCR-s), and its function has not been examined yet in human glycoprotein hormone receptors (GPHR-s). Our results indicate that the N4321.50D mutation disrupts important, architecture-stabilizing intramolecular interactions, and ultimately lead to the complete intracellular retention of the receptor. On the other hand P4492.39 is located in the intracellular part of the receptor which is important in G protein coupling. The P4492.39L mutation results in signaling impairment, with a more profound effect on the Gq/11 pathway. Conclusion TSHR mutations are common among Hungarian patients with CH. The novel genetic alterations revealed important structural role of the N4321.50 and the P4492.39 residues in receptor expression and signaling, respectively.
N1  - Megosztott els?szerz?ség Labadi A, Grassi ES és Gellen B között
ER  -