title: Frequent TSH receptor genetic alterations with variable signaling impairment in a large series of children with nonautoimmune isolated hyperthyrotropinemia.
abstract: BACKGROUND
  Heterozygous mutations in the TSH receptor gene (TSHR) are associated with partial TSH resistance, characterized by isolated nonautoimmune hyperthyrotropinemia (NAHT). The prevalence and management of this condition is controversial.
  
  
  OBJECTIVE
  Our objective was to investigate the prevalence and clinical impact of TSHR alterations in a large series of pediatric patients with NAHT and to dissect their mechanism of action.
  
  
  METHODS
  For this prospective multicenter study, clinical data and samples were collected in the clinical units and conveyed to a centralized laboratory for analysis.
  
  
  METHODS
  Subjects included 153 unrelated patients with NAHT aged <18 yr. Exclusion criteria included thyroid dysgenesis or major associated congenital defects.
  
  
  METHODS
  Parameters of thyroid function, TSHR gene analysis, and TSHR functional assays were evaluated.
  
  
  RESULTS
  The frequency of heterozygous nonpolymorphic TSHR variations was 11.8%. We identified seven previously unknown variations: a frameshift (p.Q33PfsX46), one intronic (g.IVS4+2A→G), and five novel missense (p.P162L, p.Y466C, p.I583T, p.I607T, and p.R609Q) variations. The missense variations variably affected TSHR membrane expression and G(s) and/or G(q/11) signaling. Several variations cosegregated with NAHT in the affected families. Parameters of thyroid function were similar between affected and unaffected family members.
  
  
  CONCLUSIONS
  Nonpolymorphic alterations in the TSHR gene are commonly associated with isolated NAHT in young patients, thus configuring partial TSH resistance as the most frequent inheritable cause of isolated NAHT. The identification of TSHR defects may thus be helpful for a tailored management of subclinical hypothyroidism. We provide further evidence that besides the well-known defects in G(s) signaling, TSHR genetic alternations found in NAHT may frequently impair the G(q/11) pathway.
authors: Laboratori di Ricerche Endocrino-Metaboliche, Universita degli Studi di Milano, 20100 Milano, Italy.
authors: Davide
authors: D
authors: Calebiro
authors: Giulia
authors: G
authors: Gelmini
authors: Daniela
authors: D
authors: Cordella
authors: Marco
authors: M
authors: Bonomi
authors: Franziska
authors: F
authors: Winkler
authors: Heike
authors: H
authors: Biebermann
authors: Alessandro
authors: A
authors: de Marco
authors: Federica
authors: F
authors: Marelli
authors: Domenico V
authors: DV
authors: Libri
authors: Francesco
authors: F
authors: Antonica
authors: Maria Cristina
authors: MC
authors: Vigone
authors: Marco
authors: M
authors: Cappa
authors: Caterina
authors: C
authors: Mian
authors: Alessandro
authors: A
authors: Sartorio
authors: Paolo
authors: P
authors: Beck-Peccoz
authors: Giorgio
authors: G
authors: Radetti
authors: Giovanna
authors: G
authors: Weber
authors: Luca
authors: L
authors: Persani
mesh_terms: D000293:Adolescent; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013959:Thyroid Diseases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood* / Q000378:metabolism; D014162:Transfection
chemical_list: D011989:Receptors, Thyrotropin; D013972:Thyrotropin