title: Functional analyses of C.2268dup in thyroid peroxidase gene associated with goitrous congenital hypothyroidism.
abstract: The c.2268dup mutation in thyroid peroxidase (TPO) gene was reported to be a founder mutation in Taiwanese patients with dyshormonogenetic congenital hypothyroidism (CH). The functional impact of the mutation is not well documented. In this study, homozygous c.2268dup mutation was detected in two Malaysian-Chinese sisters with goitrous CH. Normal and alternatively spliced TPO mRNA transcripts were present in thyroid tissues of the two sisters. The abnormal transcript contained 34 nucleotides originating from intron 12. The c.2268dup is predicted to generate a premature termination codon (PTC) at position 757 (p.Glu757X). Instead of restoring the normal reading frame, the alternatively spliced transcript has led to another stop codon at position 740 (p.Asp739ValfsX740). The two PTCs are located at 116 and 201 nucleotides upstream of the exons 13/14 junction fulfilling the requirement for a nonsense-mediated mRNA decay (NMD). Quantitative RT-PCR revealed an abundance of unidentified transcripts believed to be associated with the NMD. TPO enzyme activity was not detected in both patients, even though a faint TPO band of about 80 kD was present. In conclusion, the c.2268dup mutation leads to the formation of normal and alternatively spliced TPO mRNA transcripts with a consequential loss of TPO enzymatic activity in Malaysian-Chinese patients with goitrous CH.
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Ching Chin
authors.identifier: 0000-0001-9932-7967
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Harun
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Muhammad Yazid
authors.initials: MY
authors.lastname: Jalaludin
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Chor Yin
authors.initials: CY
authors.lastname: Lim
authors.affiliation: Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Khoon Leong
authors.initials: KL
authors.lastname: Ng
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia.
authors.forename: Sarni
authors.identifier: 0000-0002-9813-452X
authors.initials: S
authors.lastname: Mat Junit
mesh_terms: D002681:China; D003409:Congenital Hypothyroidism / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006042:Goiter / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007453:Iodide Peroxidase / Q000235:genetics*; D008296:Malaysia; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D007453:Iodide Peroxidase
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