Central hypothyroidism due to a TRHR mutation causing impaired ligand affinity and transactivation of Gq.

Central hypothyroidism due to a TRHR mutation causing impaired ligand affinity and transactivation of Gq.

J Clin Endocrinol Metab. 2017 Apr 17;:

Authors: García M, González de Buitrago J, Jiménez-Rosés M, Pardo L, Hinkle PM, Moreno JC

Abstract
Context: Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of TSH leading to low thyroid hormone synthesis. TRH receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood.
Objectives: Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms.
Design: All family members were phenotyped with thyroid hormone profiles, pituitary MRI, TRH test and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling.
Results: A homozygous missense mutation in TRHR (c.392T>C; p.I131T) was identified in an 8 year old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, N: 0.27-4.2; FT4: 9.52 pmol/L, N: 10.9-25.7) who was overweight (BMI: 20.4 kg/m2, p91), but normal stature (122 cm; -0.58 SD). His mother, two brothers and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3-8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the EC50 for signalling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq.
Conclusions: A novel missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.

PMID: 28419241 [PubMed - as supplied by publisher]

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