title: TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study.
abstract: BACKGROUND
  The prevalence of congenital hypothyroidism (CH) associated with mutations in the TSH receptor gene (TSHR) has not been established.
  
  
  OBJECTIVE
  We examined the frequency of TSHR mutations among patients with permanent primary CH and in the general population in Japan.
  
  
  METHODS
  We enrolled 102 patients with permanent primary CH [70 with "moderate to severe CH" (TSH, >or=10 mU/liter) and 32 with "mild CH" (TSH, 5-10 mU/liter)], who were identified through newborn screening among 353,000 newborns born in Kanagawa prefecture from October 1979 to June 2006. These subjects were tested for TSHR mutations by PCR-based direct sequencing. We further characterized molecular functions of identified mutant TSHRs in vitro.
  
  
  RESULTS
  We found three patients with moderate to severe CH who had biallelic mutations in TSHR and three patients with mild CH who had monoallelic mutations. Observed mutations included one previously characterized mutation (p.R450H) and three uncharacterized mutations (p.G132R, p.A204V, and p.D403N). In vitro experiments confirmed loss of functions of these four mutants. Among four mutations, p.R450H was particularly frequent: six of nine mutant alleles harbored p.R450H. All six alleles with p.R450H commonly carried a minor single nucleotide polymorphism, suggesting a founder effect. We estimated the prevalence of biallelic TSHR mutations to be 4.3% (three in 70) in Japanese patients with moderate to severe CH, and 1 in 118,000 (three in 353,000) in the general Japanese population.
  
  
  CONCLUSIONS
  In Japan, TSHR mutations are relatively common among patients with CH, and a founder mutation (p.R450H) accounts for about 70% of mutants.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Abe
authors.forename: Masato
authors.initials: M
authors.lastname: Yasui
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D006801:Humans; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D008297:Male; D009154:Mutation; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology; D055815:Young Adult
chemical_list: D011989:Receptors, Thyrotropin