Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2017 Apr 19

PMID 28419241

Citations 12

Authors

Marta Garcia

Jesus Gonzalez de Buitrago

Mireia Jimenez-Roses

Leonardo Pardo

Patricia M Hinkle

Jose C Moreno

Affiliations

Soon will be listed here.

Abstract

Context: Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (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 magnetic resonance imaging, TRH tests, 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, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq.

Conclusions: A unique 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.

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References

Gaborik Z, Jagadeesh G, Zhang M, Spat A, Catt K, Hunyady L . The role of a conserved region of the second intracellular loop in AT1 angiotensin receptor activation and signaling. Endocrinology. 2003; 144(6):2220-8. DOI: 10.1210/en.2002-0135. View

Rasmussen S, DeVree B, Zou Y, Kruse A, Chung K, Kobilka T . Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature. 2011; 477(7366):549-55. PMC: 3184188. DOI: 10.1038/nature10361. View

van Tijn D, de Vijlder J, Vulsma T . Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab. 2007; 93(2):410-9. DOI: 10.1210/jc.2006-2656. View

Rabeler R, Mittag J, Geffers L, Ruther U, Leitges M, Parlow A . Generation of thyrotropin-releasing hormone receptor 1-deficient mice as an animal model of central hypothyroidism. Mol Endocrinol. 2004; 18(6):1450-60. DOI: 10.1210/me.2004-0017. View

Huang H, Tao Y . Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor. J Mol Endocrinol. 2014; 53(3):319-30. DOI: 10.1530/JME-14-0184. View

Zhu C, Cook L, Hinkle P . Dimerization and phosphorylation of thyrotropin-releasing hormone receptors are modulated by agonist stimulation. J Biol Chem. 2002; 277(31):28228-37. DOI: 10.1074/jbc.M204221200. View

Burstein E, Spalding T, Brann M . The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling. J Biol Chem. 1998; 273(38):24322-7. DOI: 10.1074/jbc.273.38.24322. View

Weintraub B, Gesundheit N, Taylor T, Gyves P . Effect of TRH on TSH glycosylation and biological action. Ann N Y Acad Sci. 1989; 553:205-13. DOI: 10.1111/j.1749-6632.1989.tb46643.x. View

Hinkle P, Nelson E, Ashworth R . Characterization of the calcium response to thyrotropin-releasing hormone in lactotrophs and GH cells. Trends Endocrinol Metab. 1996; 7(10):370-4. DOI: 10.1016/s1043-2760(96)00188-9. View

10.

Gomez J, Maravall F, Gomez N, Guma A, Soler J . Determinants of thyroid volume as measured by ultrasonography in healthy adults randomly selected. Clin Endocrinol (Oxf). 2000; 53(5):629-34. DOI: 10.1111/j.1365-2265.2000.01138.x. View

11.

Moro O, Lameh J, Hogger P, Sadee W . Hydrophobic amino acid in the i2 loop plays a key role in receptor-G protein coupling. J Biol Chem. 1993; 268(30):22273-6. View

12.

Garcia M, Fernandez A, Moreno J . Central hypothyroidism in children. Endocr Dev. 2014; 26:79-107. DOI: 10.1159/000363157. View

13.

Montanelli L, Van Durme J, Smits G, Bonomi M, Rodien P, Devor E . Modulation of ligand selectivity associated with activation of the transmembrane region of the human follitropin receptor. Mol Endocrinol. 2004; 18(8):2061-73. DOI: 10.1210/me.2004-0036. View

14.

Bonomi M, Busnelli M, Beck-Peccoz P, Costanzo D, Antonica F, Dolci C . A family with complete resistance to thyrotropin-releasing hormone. N Engl J Med. 2009; 360(7):731-4. DOI: 10.1056/NEJMc0808557. View

15.

Venkatakrishnan A, Deupi X, Lebon G, Tate C, Schertler G, Babu M . Molecular signatures of G-protein-coupled receptors. Nature. 2013; 494(7436):185-94. DOI: 10.1038/nature11896. View

16.

Vroling B, Sanders M, Baakman C, Borrmann A, Verhoeven S, Klomp J . GPCRDB: information system for G protein-coupled receptors. Nucleic Acids Res. 2010; 39(Database issue):D309-19. PMC: 3013641. DOI: 10.1093/nar/gkq1009. View

17.

Fares F . The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: development of agonists and antagonists. Biochim Biophys Acta. 2006; 1760(4):560-7. DOI: 10.1016/j.bbagen.2005.12.022. View

18.

Yamada M, Mori M . Mechanisms related to the pathophysiology and management of central hypothyroidism. Nat Clin Pract Endocrinol Metab. 2008; 4(12):683-94. DOI: 10.1038/ncpendmet0995. View

19.

DeVree B, Mahoney J, Velez-Ruiz G, Rasmussen S, Kuszak A, Edwald E . Allosteric coupling from G protein to the agonist-binding pocket in GPCRs. Nature. 2016; 535(7610):182-6. PMC: 5702553. DOI: 10.1038/nature18324. View

20.

Sun Y, Bak B, Schoenmakers N, van Trotsenburg A, Oostdijk W, Voshol P . Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012; 44(12):1375-81. PMC: 3511587. DOI: 10.1038/ng.2453. View