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Licensed Unlicensed Requires Authentication Published by De Gruyter August 19, 2014

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

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


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.

Corresponding author: Helton Estrela Ramos, Federal University of Bahia, Health and Science Institute, Department of Biorregulation, Avenida Reitor Miguel Calmon, S/N, Sala 301, Vale do Canela, 40110-102 Salvador, Bahia, Brazil, Phone: +55 71 3283 8890, Fax: +55 71 3283 8927, E-mail: ,; Curso de Pós-Graduação em Biotecnologia em Saúde e Medicina Investigativa, Centro de Pesquisa Gonçalo Moniz-FIOCRUZ/BA, Salvador, Bahia, Brazil; INSERM U845, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Pediatric Endocrine Unit, Centre des Maladies Endocriniennes Rares de la Croissance, Hôpital Necker Enfants Malades, AP-HP, Paris, France; and Departamento de Biorregulação, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Bahia, Brazil


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Received: 2014-5-13
Accepted: 2014-7-14
Published Online: 2014-8-19
Published in Print: 2015-7-1

©2015 by De Gruyter

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