Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes
| Autor: | Muawia A. Ahmed, Abdellatif Bouazzaoui, Abulkareem Anazi, Wajahatullah Khan, Mohiuddin M. Taher, Naji Altayeb, Ramzia Safar, Faisal A. Al-Allaf, Naffaa Al-Harbi, Burhan M. Edrees, Zainularifeen Abduljaleel, Khawala Alansary, Howaida Al-Edressi, Mohammad Athar |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 Autosomal dominant polycystic kidney disease Biology medicine.disease_cause Biochemistry 03 medical and health sciences Phylogenetic 0302 clinical medicine Genetics medicine Gene Comparative genomics Mutation PKD1 Wild type Regular Article Autosomal recessive polycystic kidney disease (ARPKD) medicine.disease Autosomal Recessive Polycystic Kidney Disease Polycystic kidney and hepatic disease 1 (PKHD1) lcsh:Genetics 030104 developmental biology Next generation sequencing (NGS) 030220 oncology & carcinogenesis Molecular Medicine Pathogenicity prediction Biotechnology |
| Zdroj: | Genomics Data, Vol 10, Iss C, Pp 127-134 (2016) Genomics Data |
| ISSN: | 2213-5960 |
| Popis: | A targeted customized sequencing of genes implicated in autosomal recessive polycystic kidney disease (ARPKD) phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified four potential pathogenic variants in PKHD1 gene [c.4870C > T, p.(Arg1624Trp), c.5725C > T, p.(Arg1909Trp), c.1736C > T, p.(Thr579Met) and c.10628T > G, p.(Leu3543Trp)] among 12 out of 18 samples. However, one variant c.4870C > T, p.(Arg1624Trp) was common among eight patients. Some patient samples also showed few variants in autosomal dominant polycystic kidney disease (ADPKD) disease causing genes PKD1 and PKD2 such as c.12433G > A, p.(Val4145Ile) and c.1445T > G, p.(Phe482Cys), respectively. All causative variants were validated by capillary sequencing and confirmed the presence of a novel homozygous variant c.10628T > G, p.(Leu3543Trp) in a male proband. We have recently published the results of these studies (Edrees et al., 2016). Here we report for the first time the effect of the common mutation p.(Arg1624Trp) found in eight samples on the protein structure and function due to the specific amino acid changes of PKHD1 protein using molecular dynamics simulations. The computational approaches provide tool predict the phenotypic effect of variant on the structure and function of the altered protein. The structural analysis with the common mutation p.(Arg1624Trp) in the native and mutant modeled protein were also studied for solvent accessibility, secondary structure and stabilizing residues to find out the stability of the protein between wild type and mutant forms. Furthermore, comparative genomics and evolutionary analyses of variants observed in PKHD1, PKD1, and PKD2 genes were also performed in some mammalian species including human to understand the complexity of genomes among closely related mammalian species. Taken together, the results revealed that the evolutionary comparative analyses and characterization of PKHD1, PKD1, and PKD2 genes among various related and unrelated mammalian species will provide important insights into their evolutionary process and understanding for further disease characterization and management. |
| Databáze: | OpenAIRE |
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