title: A mutation in the thyroid hormone receptor alpha gene.
abstract: Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
authors.affiliation: University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Bochukova
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: Maura
authors.initials: M
authors.lastname: Agostini
authors.forename: Erik
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: Odelia
authors.initials: O
authors.lastname: Rajanayagam
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Elana
authors.initials: E
authors.lastname: Henning
authors.forename: Jana
authors.initials: J
authors.lastname: Reinemund
authors.forename: Evelien
authors.initials: E
authors.lastname: Gevers
authors.forename: Margarita
authors.initials: M
authors.lastname: Sarri
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Amaka
authors.initials: A
authors.lastname: Offiah
authors.forename: Assunta
authors.initials: A
authors.lastname: Albanese
authors.forename: David
authors.initials: D
authors.lastname: Halsall
authors.forename: John W R
authors.initials: JW
authors.lastname: Schwabe
authors.forename: Murray
authors.initials: M
authors.lastname: Bain
authors.forename: Keith
authors.initials: K
authors.lastname: Lindley
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Faraneh
authors.initials: F
authors.lastname: Vargha-Khadem
authors.forename: Faraneh Vargha
authors.initials: FV
authors.lastname: Khadem
authors.forename: Mehul
authors.initials: M
authors.lastname: Dattani
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: D002648:Child; D018389:Codon, Nonsense; D005260:Female; D006130:Growth Disorders / Q000188:drug therapy / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy / Q000235:genetics*; D008958:Models, Molecular; D011487:Protein Conformation; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry / Q000235:genetics*; D013963:Thyroid Hormones / Q000097:blood; D013974:Thyroxine / Q000097:blood* / Q000627:therapeutic use*; D014284:Triiodothyronine / Q000097:blood*
chemical_list: D018389:Codon, Nonsense; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D014284:Triiodothyronine; D013974:Thyroxine