Genomics & Informatics

  • 제19권3호
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  • Pages.29.1-29.10
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  • 2021
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  • 1598-866X(pISSN)
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  • 2234-0742(eISSN)
한국유전체학회 (Korea Genome Organization)
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Molecular insights into the role of genetic determinants of congenital hypothyroidism

  • Kollati, Yedukondalu (Department of Biotechnology, Vignan's University) ;
  • Akella, Radha Rama Devi (Department of Genetics, Rainbow Children's Hospital) ;
  • Naushad, Shaik Mohammad (Department of Biochemical Genetics and Pharmacogenomics, Sandor Speciality Diagnostics Pvt. Ltd) ;
  • Patel, Rajesh K. (Department of Genetics, Genetic Group of Gujarat Diagnostic Centre) ;
  • Reddy, G. Bhanuprakash (Biochemistry Division, National Institute of Nutrition) ;
  • Dirisala, Vijaya R. (Department of Biotechnology, Vignan's University)
  • 투고 : 2021.06.14
  • 심사 : 2021.07.22
  • 발행 : 2021.09.30
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초록

In our previous studies, we have demonstrated the association of certain variants of the thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), and thyroglobulin (TG) genes with congenital hypothyroidism. Herein, we explored the mechanistic basis for this association using different in silico tools. The mRNA 3'-untranslated region (3'-UTR) plays key roles in gene expression at the post-transcriptional level. In TSHR variants (rs2268477, rs7144481, and rs17630128), the binding affinity of microRNAs (miRs) (hsa-miR-154-5p, hsa-miR-376a-2-5p, hsa-miR-3935, hsa-miR-4280, and hsa-miR-6858-3p) to the 3'-UTR is disrupted, affecting post-transcriptional gene regulation. TPO and TG are the two key proteins necessary for the biosynthesis of thyroid hormones in the presence of iodide and H2O2. Reduced stability of these proteins leads to aberrant biosynthesis of thyroid hormones. Compared to the wild-type TPO protein, the p.S398T variant was found to exhibit less stability and significant rearrangements of intra-atomic bonds affecting the stoichiometry and substrate binding (binding energies, ΔG of wild-type vs. mutant: -15 vs. -13.8 kcal/mol; and dissociation constant, Kd of wild-type vs. mutant: 7.2E-12 vs. 7.0E-11 M). The missense mutations p.G653D and p.R1999W on the TG protein showed altered ΔG(0.24 kcal/mol and 0.79 kcal/mol, respectively). In conclusion, an in silico analysis of TSHR genetic variants in the 3'-UTR showed that they alter the binding affinities of different miRs. The TPO protein structure and mutant protein complex (p.S398T) are less stable, with potentially deleterious effects. A structural and energy analysis showed that TG mutations (p.G653D and p.R1999W) reduce the stability of the TG protein and affect its structure-functional relationship.

키워드

과제정보

This work was partly supported by a grant from DST-SERB, Government of India (ECR/2016/00304). The authors specially thank Dr. Pasumarthi NBS Srinivas, Dr. Hari Krishna K, Dr. Bajarang Vasant Kumbhar, Anusha Puvvada, Uma Maheshwar P for their support during the investigation.

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