Molecular insights into the role of genetic determinants of congenital hypothyroidism

Abstract

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.

A bioinformatics-based analysis of chromatin regulators in atrial fibrillation uncovers potential novel biomarkers and immune infiltration characteristics

“…14 post-transcriptional (miRNAs) regulatory signatures regulated with them were determined.According to the miRNA-hub genes network and immune in ltration analysis,Hsa-miR-142-3p,hsa-miR-639,hsa-miR-3681,and hsa-miR-4280 were selected as potential therapeutic targets for AF.Among them, Aberrant activation of hsa-miR-142-3p can increase the expression of the target molecule BCL2L1, thus enabling excessive apoptosis of endothelial cells in hypertensive patients [26].Hsa-MiR-639 can be used as a biomarker to predict whether pediatric dilated cardiomyopathy can recover from after cardiac transplantation [27].By sponging hsa-miR-3681,SIRT1 gene could promote autophagy in inhibiting cardiac hypertrophy [28].Hsa-miR-4280 is disrupted in thyroid-stimulating hormone receptor variants, affecting post-transcriptional gene regulation [29].…”

Speculating on the Evolutionary Pathway of the Hypothalamus-Pituitary-Thyroid Axis

“…In addition to known mutations, the role of single nucleotide polymorphisms (SNPs) has been also investigated in CH. Different studies reported as polymorphic variants in TPO, TSHR and TG genes can represent a genetic risk factor for dishormonogentic CH [7][8][9][10].…”