Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

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

Loss-of-Function Variants in a Hungarian Cohort Reveal Structural Insights on TSH Receptor Maturation and Signaling

K