ESPE Abstracts (2016) 86 RFC11.1

Central Hypothyroidism and Biallelic Defect Near the D/ERY Motif of the TRHR Gene

Marta Garcíaa, Jesús González de Buitragob, Leonardo Pardoc, Patricia M. Hinkled & José C. Morenoa

aThyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital. Madrid, Spain. Autonomous University of Madrid, Madrid, Spain; bDepartment of Pediatrics, San Pedro de Alcántara Hospital, Cáceres, Spain; cComputational Medicine Laboratory, Biostatistics Unit, Medicine Faculty, Autonomous University of Barcelona, Barcelona, Spain; dDepartment of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA

Background: The TRH receptor (TRHR) is a G-protein coupled receptor activated by hypothalamic TRH. In thyrotropes, TRH-TRHR signalling controls synthesis, secretion and bioactivity of TSH. Human TRHR defects are extremely rare, and only three cases are known with central hypothyroidism and short stature as variable presenting feature.

Objective and hypotheses: Phenotypical characterization of a family with suspected central hypothyroidism and investigation of the molecular mechanism underlying the disorder.

Method: Mutation screening of the TRH, TRHR and TSHB genes in seven individuals of a consanguineous pedigree. Determination of membrane expression, ligand affinity and transactivation properties of a TRHR mutant using ELISA, ligand ([3H]MeTRH) binding and luciferase reporter assays, respectively.

Results: A homozygous missense mutation in TRHR was identified (c.392T>C; p.I131T) in an 8 year old boy with mild central hypothryoidism (FT4: 0.74 ng/dl, TSH: 2.61 mIU/mL) and overweight, but normal stature. TRH test showed borderline-low TSH response, indicating pituitary hypothyroidism. The parents, three siblings and grandmother of the index patient were heterozygotes for the mutation, and showed isolated TSH elevation (4.6–8 mIU/L). The mutation localises in the 2nd intracellular loop of the TRHR, adjacent to the D/ERY motif involved in G protein activation. The I131T mutant does not interfere with the receptor trafficking to the membrane, but decreases its affinity to the TRH ligand (wild type=9.1±0.4 nM vs mutant=3.1±0.3 nM) and impairs transactivation of an AP1-containing promoter by TRH (wild type EC50=2.8±0.9 nM vs mutant EC50=20.4±0.8 nM).

Conclusion: A novel defect in TRHR causes central hypothyroidism in the homozygous state but leads to hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The mutation impairs TRH-TRHR signalling by decreasing the affinity of receptor for TRH and suggests incomplete activation of G-proteins by dysfunction of the D/ERY motif.

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