title: Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients.
abstract: BACKGROUND
  The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2.
  
  
  METHODS
  We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence.
  
  
  RESULTS
  The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells.
  
  
  CONCLUSIONS
  TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA.
  
  
  BACKGROUND
  Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Carla
authors: C
authors: Moran
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Maura
authors: M
authors: Agostini
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: W Edward
authors: WE
authors: Visser
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Erik
authors: E
authors: Schoenmakers
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Nadia
authors: N
authors: Schoenmakers
authors: Academic Unit of Child Health, University of Sheffield, Sheffield, UK.
authors: Amaka C
authors: AC
authors: Offiah
authors: Department of Rheumatology, Addenbrooke's Hospital, Cambridge, UK.
authors: Ken
authors: K
authors: Poole
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Odelia
authors: O
authors: Rajanayagam
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Greta
authors: G
authors: Lyons
authors: Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.
authors: David
authors: D
authors: Halsall
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors: Mark
authors: M
authors: Gurnell
authors: Department of Paediatrics, Division of Endocrinology, Medical School University of Patras, Patras, Greece.
authors: Dionisios
authors: D
authors: Chrysis
authors: Department of Paediatrics, Division of Endocrinology, Medical School University of Patras, Patras, Greece.
authors: Alexandra
authors: A
authors: Efthymiadou
authors: Department of Child Health, King's College Hospital, London, UK.
authors: Charles
authors: C
authors: Buchanan
authors: Department of Endocrinology, King's College Hospital, London, UK.
authors: Simon
authors: S
authors: Aylwin
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. Electronic address: kkc1@medschl.cam.ac.uk.
authors: Krishna K
authors: KK
authors: Chatterjee
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D005192:Family Health; D005260:Female; D020235:Gait Apraxia / Q000209:etiology; D006579:Heterozygote; D006801:Humans; D008297:Male; D058627:Megalencephaly / Q000209:etiology; D008875:Middle Aged; D020125:Mutation, Missense; D011127:Polyps / Q000209:etiology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology; D013064:Speech Disorders / Q000209:etiology; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D018382:Thyroid Hormone Resistance Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D013974:Thyroxine / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D013974:Thyroxine