title: 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.
abstract: BACKGROUND
  Thyroid dysgenesis may be associated with loss-of-function mutations in the thyrotropin receptor (TSHR) gene.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Taise Lima Oliveira
authors.initials: TL
authors.lastname: Cerqueira
authors.forename: Aurore
authors.initials: A
authors.lastname: Carré
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevrier
authors.forename: Gabor
authors.initials: G
authors.lastname: Szinnai
authors.forename: Elodie
authors.initials: E
authors.lastname: Tron
authors.forename: Juliane
authors.initials: J
authors.lastname: Léger
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cabrol
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Queinnec
authors.forename: Nicolas
authors.initials: N
authors.lastname: De Roux
authors.forename: Mireille
authors.initials: M
authors.lastname: Castanet
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Helton Estrela
authors.identifier: http://orcid.org/0000-0002-2900-2099
authors.initials: HE
authors.lastname: Ramos
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003430:Cross-Sectional Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D050033:Thyroid Dysgenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D011989:Receptors, Thyrotropin