title: The coexistence of a novel inactivating mutant thyrotropin receptor allele with two thyroid peroxidase mutations: a genotype-phenotype correlation.
abstract: BACKGROUND
  TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual.
  
  
  METHODS
  Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs.
  
  
  RESULTS
  A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation.
  
  
  CONCLUSIONS
  TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Chutintorn
authors.initials: C
authors.lastname: Sriphrapradang
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
authors.forename: Mia
authors.initials: M
authors.lastname: Weiss
authors.forename: Marla S
authors.initials: MS
authors.lastname: Barkoff
authors.forename: Osnat
authors.initials: O
authors.lastname: Admoni
authors.forename: Dallasheh
authors.initials: D
authors.lastname: Kawthar
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Caltabiano
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000704:Analysis of Variance; D018912:Arabs / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006981:Hyperthyroxinemia / Q000235:genetics* / Q000503:physiopathology; D007223:Infant; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000503:physiopathology
chemical_list: D011989:Receptors, Thyrotropin; D007453:Iodide Peroxidase