title: Congenital hypothyroidism caused by a premature termination signal in exon 10 of the human thyroid peroxidase gene.
abstract: The molecular basis of a total iodide organification defect causing severe congenital hypothyroidism has been elucidated. The defect occurred in a family in which two of five siblings were affected. Thyroid tissue from one patient was available for investigation. The total thyroid peroxidase (TPO) messenger ribonucleic acid level was reduced and consisted mainly of the alternatively spliced form of TPO missing exon 10 (TPO-2). No TPO-1 (wild-type) protein was detected by Western blotting. The TPO-2 translation product of a slightly smaller mol wt was present in thyroid tissue of this patient. TPO activity was absent and thyroglobulin was not iodinated, showing that iodination in vivo did not occur. Denaturing gradient gel electrophoresis and subsequent sequencing revealed in both alleles of the patients a C-->T transition of nucleotide 1708 of the TPO gene, involving a CpG dinucleotide. The mutation introduces a premature termination signal in exon 10 of the TPO gene, preventing the synthesis of enzymatic active peroxidase.
authors.affiliation: Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Bikker
authors.forename: J J
authors.initials: JJ
authors.lastname: Waelkens
authors.forename: B
authors.initials: B
authors.lastname: Bravenboer
authors.forename: J J
authors.initials: JJ
authors.lastname: de Vijlder
mesh_terms: D000328:Adult; D001483:Base Sequence; D003409:Congenital Hypothyroidism; D004247:DNA / Q000235:genetics; D005091:Exons; D005796:Genes; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007453:Iodide Peroxidase / Q000172:deficiency / Q000235:genetics*; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D010375:Pedigree; D010454:Peptide Termination Factors; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012313:RNA / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D015335:Molecular Probes; D010454:Peptide Termination Factors; D012313:RNA; D004247:DNA; D007453:Iodide Peroxidase