title: Molecular basis of thyroid dyshormonogenesis: genetic screening in population-based Japanese patients.
abstract: BACKGROUND
  Inborn errors of thyroid hormone biosynthesis are collectively referred to as thyroid dyshormonogenesis (DH). Seven genes have been implicated in DH, including the dual oxidase 2 gene (DUOX2), the thyroglobulin gene (TG), and the thyroid peroxidase gene (TPO).
  
  
  OBJECTIVE
  We aimed to define the prevalence and phenotypic spectrum of DH with single gene mutations.
  
  
  METHODS
  A population-based cohort of 102 patients with permanent congenital hypothyroidism was enrolled. Fourteen were diagnosed as DH and were analyzed for the seven causative genes including DUOX2, TG, and TPO. Several common mutations were screened in the remaining 88 patients. Pathogenicity of single amino acid mutations was verified in vitro.
  
  
  RESULTS
  We identified four, five, and two patients with seemingly biallelic mutations in DUOX2, TG, and TPO, respectively. We also found two patients having one heterozygous DUOX2 mutation and one uncommon single-nucleotide polymorphism (SNP) p.H678R (rs57659670, allele frequency 0.035) and another two patients with homozygous p.H678R. Expression experiments and RT-PCR revealed that p.H678R is a functional SNP with theoretical 40% loss of function, supporting a role of p.H678R in the onset of DH. As for clinical phenotypes, patients with inactive DUOX2 alleles (mutations and/or p.H678R) showed characteristic time-dependent improvement of thyroid function and morphology. All three evaluated patients had a negative result in the perchlorate test.
  
  
  CONCLUSIONS
  Mutations (or a functional SNP) in DUOX2, TG, or TPO were observed in 93% (95% confidence interval = 70-99%) of DH patients. Inactive DUOX2 alleles cause a broader phenotypic spectrum than currently accepted.
authors: Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Satoshi
authors: S
authors: Narumi
authors: Koji
authors: K
authors: Muroya
authors: Yumi
authors: Y
authors: Asakura
authors: Masanori
authors: M
authors: Aachi
authors: Tomonobu
authors: T
authors: Hasegawa
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D006801:Humans; D007564:Japan; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000503:physiopathology*