RESUMEN
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 as yet. OBJECTIVE: We aimed to explore TSH receptor (TSHR) mutations in a cohort of Hungarian patients with CH. PATIENTS: Eighty-five 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 four patients (one heterozygous and three compound heterozygous), seven TSHR mutations were identified. Among these, N432(1.50)D and P449(2.39)L are novel missense alterations. Importantly, the N432(1.50) residue is highly conserved among G protein-coupled receptors, and its function has not been examined yet in human glycoprotein hormone receptors. Our results indicate that the N432(1.50)D mutation disrupts important, architecture-stabilizing intramolecular interactions and ultimately leads to the complete intracellular retention of the receptor. On the other hand, P449(2.39) is located in the intracellular part of the receptor, which is important in G protein coupling. The P449(2.39)L 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 an important structural role of the N432(1.50) and the P449(2.39) residues in receptor expression and signaling, respectively.