title: Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism.
abstract: OBJECTIVE
  Thyroid peroxidase (TPO) deficiency is one of the causes of thyroid dyshormonogenesis, because TPO plays a key role in thyroid hormone biosynthesis. To determine the frequency and pattern of TPO abnormalities, we have been screening TPO genes of patients with congenital goitrous hypothyroidism.
  
  
  METHODS
  TPO genes of a patient with congenital goitrous hypothyroidism and her parents were directly sequenced, and two novel missense mutations (R665W and G771R) were found. The former was derived from her father and the latter from her mother. R665 and G771 were well conserved in the peroxidase superfamily. When mRNAs containing each of the mutations were transfected into CHO-K1 cells, each cell showed faint TPO enzyme activity. However, immunofluorescence and immunoelectron microscopic analyses revealed that neither of the mutated TPOs reached the plasma membrane.
  
  
  CONCLUSIONS
  Two novel missense mutations in the TPO gene were found. TPO proteins encoded by these mutated alleles showed abnormal cellular localization; namely, localization on the plasma membrane was disturbed. The loss of plasma membrane localization in mutated TPOs brought about the iodide organification defect, which was diagnosed as congenital hypothyroidism.
authors.affiliation: Laboratory for Clinical Investigation, Miyazaki Medical College, Kihara 5200, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Umeki
authors.forename: Tomio
authors.initials: T
authors.lastname: Kotani
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawano
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suganuma
authors.forename: Ikuo
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Yatsuki
authors.initials: Y
authors.lastname: Aratake
authors.forename: Mahoko
authors.initials: M
authors.lastname: Furujo
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ichiba
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002675:Child, Preschool; D003409:Congenital Hypothyroidism; D006224:Cricetinae; D005260:Female; D006042:Goiter / Q000151:congenital / Q000235:genetics; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D007454:Iodides / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D014018:Tissue Distribution
chemical_list: D007454:Iodides; D007453:Iodide Peroxidase