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Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion

Cerqueira, Taise Lima Oliveira ; Carré, Aurore ; Chevrier, Lucie ; Szinnai, Gabor ; Tron, Elodie ; Léger, Juliane ; Cabrol, Sylvie ; Queinnec, Chrystelle ; De Roux, Nicolas ; Castanet, Mireille ; Polak, Michel ; Ramos, Helton Estrela

In: Journal of Pediatric Endocrinology and Metabolism, 2015, vol. 28, no. 7-8, p. 777-784

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    Titre
    • Functional characterization of the novel sequence variant p.S304R in the hinge region of TSHR in a congenital hypothyroidism patients and analogy with other formerly known mutations of this gene portion
    Auteur
    • Cerqueira, Taise Lima Oliveira
    • Carré, Aurore. INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
    • Chevrier, Lucie. Pediatric Endocrine Unit, Hôpital Armand Trousseau, AP-HP, Paris, France
    • Szinnai, Gabor. Pediatric Endocrinology, University Children's Hospital Basel, University Basel, Switzerland
    • Tron, Elodie. INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
    • Léger, Juliane. Pediatric Endocrine Unit, Centre des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, AP-HP, Paris, France
    • Cabrol, Sylvie. Pediatrics department, CHU, Bordeaux, France
    • Queinnec, Chrystelle. Pediatrics department, CH de Cornouailles-hopital Laennec, Quimper, France
    • De Roux, Nicolas. Pediatric Endocrine Unit, Hôpital Armand Trousseau, AP-HP, Paris, France
    • Castanet, Mireille
    • Polak, Michel
    • Ramos, Helton Estrela. E-mail: ramoshelton@gmail.com
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Journal of Pediatric Endocrinology and Metabolism, 2015, vol. 28, no. 7-8, p. 777-784. De Gruyter
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:325696
    Summary
    Context: Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene. Objectives: The aim of this study was to characterize a novel TSHR gene variant found in one patient harboring congenital hypothyroidism (CH) from a cohort of patients with various types of thyroid defects. Materials and methods: This cross-sectional cohort study involved 118 patients with CH and their family members, including 45 with familial and 73 with sporadic diseases. The thyroid gland was normal in 23 patients, 25 patients had hypoplasia, 25 hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Genomic DNA was extracted, and 10 exons of the TSHR gene were amplified and sequenced. Mutations in other candidate genes were investigated. Ortholog alignment was performed, and TSHR functional assays were evaluated. Results: We identified one previously unknown missense variation in the hinge region (HinR) of the TSHR gene (p.S304R) in one patient with thyroid hypoplasia. This variant is conserved in our ortholog alignment. However, the p.S304R TSHR variant presented a normal glycosylation pattern and signal transduction activity in functional analysis. Conclusion: We report the ocurrence of a novel nonsynonymous substitution in the HinR of the large N-terminal extracellular domain of the TSHR gene in a patient with thyroid hypoplasia. In contrast with four others in whom TSHR mutations of the hinge portion were previously identified, the p.S304R TSHR variation neither affected TSH binding nor cAMP pathway activation. This TSHR gene variant was documented in a CH patient, but the current data do not support its role in the clinical phenotype.