title: A Novel Thyrotropin-Releasing Hormone Receptor Missense Mutation (P81R) in Central Congenital Hypothyroidism.
abstract: BACKGROUND
  Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH β subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene.
  
  
  METHODS
  A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2.
  
  
  CONCLUSIONS
  Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: O
authors.initials: O
authors.lastname: Koulouri
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: A K
authors.initials: AK
authors.lastname: Nicholas
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: E
authors.initials: E
authors.lastname: Schoenmakers
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Mokrosinski
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Lane
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: T
authors.initials: T
authors.lastname: Cole
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: I S
authors.initials: IS
authors.lastname: Farooqi
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: V K
authors.initials: VK
authors.lastname: Chatterjee
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Gurnell
authors.affiliation: Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; West Midlands Regional Genetics Service (F.L., T.C.), Birmingham Women's Hospital NHS Foundation Trust, Birmingham B15 2TG, United Kingdom; and Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Schoenmakers
mesh_terms: D003409:Congenital Hypothyroidism / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D020125:Mutation, Missense; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000235:genetics*
chemical_list: D018025:Receptors, Thyrotropin-Releasing Hormone