Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling

Árpád Lábadi, Elisa Stellaria Grassi, Balázs Gellén, Gunnar Kleinau, Heike Biebermann, Beáta Ruzsa, Giulia Gelmini, Orsolya Rideg, Attila Miseta, Gábor L. Kovács, Attila Patócs, Eniko Felszeghy, Endre V. Nagy, Emese Mezosi, Luca Persani

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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, N4321.50D and P4492.39L are novel missense alterations. Importantly, theN4321.50 residueis highlyconservedamongGprotein-coupledreceptors,anditsfunctionhas not been examined yet in human glycoprotein hormone receptors. Our results indicate that the N4321.50D mutation disrupts important, architecture-stabilizing intramolecular interactions and ultimately leads 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 inGprotein 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 an important structural role of the N4321.50 and the P4492.39 residues in receptor expression and signaling, respectively.

Original languageEnglish
Pages (from-to)E1039-E1045
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number7
DOIs
Publication statusPublished - Jul 1 2015

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Thyrotropin Receptors
Congenital Hypothyroidism
Mutation
Screening
Newborn Infant
Exons
Glycoproteins
Molecular Models
Hungary
Genes
Hormones
Thyroid Gland
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling. / Lábadi, Árpád; Grassi, Elisa Stellaria; Gellén, Balázs; Kleinau, Gunnar; Biebermann, Heike; Ruzsa, Beáta; Gelmini, Giulia; Rideg, Orsolya; Miseta, Attila; Kovács, Gábor L.; Patócs, Attila; Felszeghy, Eniko; Nagy, Endre V.; Mezosi, Emese; Persani, Luca.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 7, 01.07.2015, p. E1039-E1045.

Research output: Contribution to journalArticle

Lábadi, Á, Grassi, ES, Gellén, B, Kleinau, G, Biebermann, H, Ruzsa, B, Gelmini, G, Rideg, O, Miseta, A, Kovács, GL, Patócs, A, Felszeghy, E, Nagy, EV, Mezosi, E & Persani, L 2015, 'Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 7, pp. E1039-E1045. https://doi.org/10.1210/jc.2014-4511
Lábadi, Árpád ; Grassi, Elisa Stellaria ; Gellén, Balázs ; Kleinau, Gunnar ; Biebermann, Heike ; Ruzsa, Beáta ; Gelmini, Giulia ; Rideg, Orsolya ; Miseta, Attila ; Kovács, Gábor L. ; Patócs, Attila ; Felszeghy, Eniko ; Nagy, Endre V. ; Mezosi, Emese ; Persani, Luca. / Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 7. pp. E1039-E1045.
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abstract = "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, N4321.50D and P4492.39L are novel missense alterations. Importantly, theN4321.50 residueis highlyconservedamongGprotein-coupledreceptors,anditsfunctionhas not been examined yet in human glycoprotein hormone receptors. Our results indicate that the N4321.50D mutation disrupts important, architecture-stabilizing intramolecular interactions and ultimately leads 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 inGprotein 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 an important structural role of the N4321.50 and the P4492.39 residues in receptor expression and signaling, respectively.",
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T1 - Loss-of-function variants in a hungarian cohort reveal structural insights on TSH receptor maturation and signaling

AU - Lábadi, Árpád

AU - Grassi, Elisa Stellaria

AU - Gellén, Balázs

AU - Kleinau, Gunnar

AU - Biebermann, Heike

AU - Ruzsa, Beáta

AU - Gelmini, Giulia

AU - Rideg, Orsolya

AU - Miseta, Attila

AU - Kovács, Gábor L.

AU - Patócs, Attila

AU - Felszeghy, Eniko

AU - Nagy, Endre V.

AU - Mezosi, Emese

AU - Persani, Luca

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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 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, N4321.50D and P4492.39L are novel missense alterations. Importantly, theN4321.50 residueis highlyconservedamongGprotein-coupledreceptors,anditsfunctionhas not been examined yet in human glycoprotein hormone receptors. Our results indicate that the N4321.50D mutation disrupts important, architecture-stabilizing intramolecular interactions and ultimately leads 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 inGprotein 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 an important structural role of the N4321.50 and the P4492.39 residues in receptor expression and signaling, respectively.

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