Mutation Spectrum in TPO Gene of Bangladeshi Patients with Thyroid Dyshormonogenesis and Analysis of the Effects of Different Mutations on the Structural Features and Functions of TPO Protein through In Silico Approach

• Published in: BioMed research international Vol. 2019; pp. 9218903 - 18
• Main Authors: Begum, Mst. Noorjahan, Islam, Md Tarikul, Hossain, Shekh Rezwan, Bhuyan, Golam Sarower, Halim, Mohammad A., Shahriar, Imrul, Sarker, Suprovath Kumar, Haque, Shahinur, Konika, Tasnia Kawsar, Islam, Md. Sazzadul, Rahat, Asifuzzaman, Qadri, Syeda Kashfi, Sultana, Rosy, Begum, Suraiya, Sultana, Sadia, Saha, Narayan, Hasan, Mizanul, Hasanat, M. A., Banu, Hurjahan, Shekhar, Hossain Uddin, Chowdhury, Emran Kabir, Sajib, Abu A., Islam, Abul B. M. M. K., Qadri, Syed Saleheen, Qadri, Firdausi, Akhteruzzaman, Sharif, Mannoor, Kaiissar
• Format: Journal Article
• Language: English
• Published: United States Hindawi 01.01.2019; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Adolescent; Amino Acid Substitution - genetics; Amino acids; Analysis; Autoantigens - chemistry; Autoantigens - genetics; Bangladesh - epidemiology; Binding energy; Biosynthesis; Child; Child, Preschool; Computer Simulation; Computer software industry; Congenital diseases; Congenital Hypothyroidism - epidemiology; Congenital Hypothyroidism - genetics; Congenital Hypothyroidism - pathology; Defects; Deoxyribonucleic acid; Development and progression; DNA; Enzymes; Ethylenediaminetetraacetic acid; Etiology; Female; Force and energy; Gene sequencing; Genetic aspects; Genetic disorders; Genotype; Heme; Homology; Hormones; Humans; Hypothyroidism; Iodide peroxidase; Iodide Peroxidase - chemistry; Iodide Peroxidase - genetics; Iron-Binding Proteins - chemistry; Iron-Binding Proteins - genetics; Kinases; Male; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Mutation; Mutation - genetics; Patients; Peroxidase; Phenotype; Physical chemistry; Prostheses; Protein structure; Proteins; Quantum mechanics; Residues; Structure-Activity Relationship; Studies; Temperature effects; Thermal cycling; Thyroid; Thyroid gland; Thyroid Gland - metabolism; Thyroid Gland - pathology; Thyroid hormones; Bangladesh; United States; United States > US
• ISSN: 2314-6133; 2314-6141
• DOI: 10.1155/2019/9218903

Although thyroid dyshormonogenesis (TDH) accounts for 10-20% of congenital hypothyroidism (CH), the molecular etiology of TDH is unknown in Bangladesh. Thyroid peroxidase (TPO) is most frequently associated with TDH and the present study investigated the spectrum of TPO mutations in Bangladeshi patients and analyzed the effects of mutations on TPO protein structure through in silico approach. Sequencing-based analysis of TPO gene revealed four mutations in 36 diagnosed patients with TDH including three nonsynonymous mutations, namely, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, and one synonymous mutation p.Pro715Pro. Homology modelling-based analysis of predicted structures of MPO-like domain (TPO142-738) and the full-length TPO protein (TPO1-933) revealed differences between mutant and wild type structures. Molecular docking studies were performed between predicted structures and heme. TPO1-933 predicted structure showed more reliable results in terms of interactions with the heme prosthetic group as the binding energies were -11.5 kcal/mol, -3.2 kcal/mol, -11.5 kcal/mol, and -7.9 kcal/mol for WT, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, respectively, implying that p.Ala373Ser and p.Thr725Pro mutations were more damaging than p.Ser398Thr. However, for the TPO142-738 predicted structures, the binding energies were -11.9 kcal/mol, -10.8 kcal/mol, -2.5 kcal/mol, and -5.3 kcal/mol for the wild type protein, mutant proteins with p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro substitutions, respectively. However, when the interactions between the crucial residues including residues His239, Arg396, Glu399, and His494 of TPO protein and heme were taken into consideration using both TPO1-933 and TPO142-738 predicted structures, it appeared that p.Ala373Ser and p.Thr725Pro could affect the interactions more severely than the p.Ser398Thr. Validation of the molecular docking results was performed by computer simulation in terms of quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulation. In conclusion, the substitutions mutations, namely, p.Ala373Ser, p.Ser398Thr, and p.Thr725Pro, had been involved in Bangladeshi patients with TDH and molecular docking-based study revealed that these mutations had damaging effect on the TPO protein activity.