title: Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes.
abstract: 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 inPKHD1gene [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 genesPKD1andPKD2such 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 inPKHD1,PKD1, andPKD2genes 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 ofPKHD1,PKD1, andPKD2genes among various related and unrelated mammalian species will provide important insights into their evolutionary process and understanding for further disease characterization and management.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Saudi Arabia.
authors.forename: Burhan M
authors.initials: BM
authors.lastname: Edrees
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.
authors.forename: Zainularifeen
authors.initials: Z
authors.lastname: Abduljaleel
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Molecular Diagnostics Unit, Department of Laboratory and Blood Bank, King Abdullah Medical City, Makkah 21955, Saudi Arabia.
authors.forename: Faisal A
authors.initials: FA
authors.lastname: Al-Allaf
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.
authors.forename: Mohiuddin M
authors.initials: MM
authors.lastname: Taher
authors.affiliation: Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, P.O. Box 3660, Riyadh 11426, Saudi Arabia.
authors.forename: Wajahatullah
authors.initials: W
authors.lastname: Khan
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia; Science and Technology Unit, Umm Al Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Bouazzaoui
authors.affiliation: Department of Pediatric, King Faisal Specialist Hospital and Research Centre, P.O. Box 40047, Jeddah 21499, Saudi Arabia.
authors.forename: Naffaa
authors.initials: N
authors.lastname: Al-Harbi
authors.affiliation: Madinah Maternity and Children's Hospital, P.O. Box 5073, Madinah 42318, Saudi Arabia.
authors.forename: Ramzia
authors.initials: R
authors.lastname: Safar
authors.affiliation: Madinah Maternity and Children's Hospital, P.O. Box 5073, Madinah 42318, Saudi Arabia.
authors.forename: Howaida
authors.initials: H
authors.lastname: Al-Edressi
authors.affiliation: King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Saudi Arabia.
authors.forename: Khawala
authors.initials: K
authors.lastname: Alansary
authors.affiliation: King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Saudi Arabia.
authors.forename: Abulkareem
authors.initials: A
authors.lastname: Anazi
authors.affiliation: King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Saudi Arabia.
authors.forename: Naji
authors.initials: N
authors.lastname: Altayeb
authors.affiliation: King Salman Armed Forces Hospital, P.O. box 100, Tabuk, Saudi Arabia.
authors.forename: Muawia A
authors.initials: MA
authors.lastname: Ahmed
keywords: Autosomal recessive polycystic kidney disease (ARPKD); Next generation sequencing (NGS); Pathogenicity prediction; Phylogenetic; Polycystic kidney and hepatic disease 1 (PKHD1)