Abstract
Thyroid peroxidase (TPO) is the key enzyme in the biosynthesis of thyroid hormones. We aimed to identify the spectrum of mutations in the TPO gene leading to hypothyroidism in the population of West Bengal to establish the genetic etiology of the disease. 200 hypothyroid patients (case) and their corresponding sex and age matched 200 normal individuals (control) were screened depending on their clinical manifestations. Genomic DNA was isolated from peripheral blood samples and TPO gene (Exon 7 to Exon 14) was amplified by PCR. The PCR products were subjected to sequencing to identify mutations. Single nucleotide changes such as Glu 641 Lys, Asp 668 Asn, Thr 725 Pro, Asp 620 Asn, Ser 398 Thr, and Ala 373 Ser were found. Changes in the TPO were assayed in vitro to compare mutant and wild-type activities. Five mutants were enzymatically inactive in the guaiacol and iodide assays. This is a strong indication that the mutations are present at crucial positions of the TPO gene, resulting in inactivated TPO. The results of this study may help to develop a genetic screening protocol for goiter and hypothyroidism in the population of West Bengal.
Highlights
Thyroid peroxidase (TPO) is a membrane-bound glycoprotein (102 kDa), found as a dimer [1]
Amplicon size 433 474 444 485 446 449 485 238 mutations/polymorphisms in TPO gene and their effects on the function of TPO gene leading to hypothyroidism in the population of West Bengal to establish the genetic etiology of the disease
Age and sex matched subjects with no goitre, no clinical evidence of hypothyroidism, and normal levels of serum T3, free T4 (FT4), TSH, and anti-TPO antibody were enrolled as normal
Summary
Each monomer consists of 933 amino acid residues and contains a peroxidase domain, three additional extracellular domains, a transmembrane helix, and a short C-terminal intracellular tail [2]. The human TPO gene is located on chromosome 2p25 and spans approximately 150 Kb, containing 17 exons [3]. Mutations in TPO gene ( nonsynonymous cSNPs) can lead to severe defects in thyroid hormone production, due to total iodide organification defects (TIOD) or partial iodide organification defects (PIOD). Iodination of salt is the most effective and sustainable long-term public health measure for the prevention and control of iodide organification defects (IDD). The iodination programme will not be effective if the gene mutations are the cause of dyshormonogenesis. It is important to screen the percentage of people having gene mutations and iodine deficiency among the clinically identified thyroid patients
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