EXOME SEQUENCING COUPLED WITH IN SILICO FUNCTIONAL ANALYSIS IN CONSANGUINEOUS PAKISTANI FAMILIES INHERITING BREAST CANCER DETERMINED THE FOUNDER EFFECT OF THE MUTATION C.1961DUPA (P.TYR655VALFS18*) IN THE BRCA1 GENE
Main Article Content
Keywords
Breast Cancer, Pakistani, Mutation, Dominant, BRCA1, Exon
Abstract
Mutations in several genes are now known to cause susceptibility to breast cancer. In Pakistan, very little is known about the genetic spectrum of Breast cancer. So, the main aim of the current genetic study was to investigate the four unrelated Saraiki origin consanguineous Pakistani families segregating breast cancer. Methodology for genetic analysis includes Whole Exome Sequencing (WES) and Sanger sequencing; however, in silico functional analysis was done using I-TASSER (for 3D structure modeling and Cluspro tool (for Protein-Protein interaction). Analysis of exome data identified previously reported frameshift heterozygous duplication mutation c.1961dupA (p.Tyr655Valfs18*) in the 10th exon of the BRCA1 gene inherited in the autosomal dominant pattern in all the families. No symptoms were found in the male individuals of the families. In silico functional analysis also revealed the mutation's adverse effect on protein structure and interaction. We hypothesized on the evolutionary importance of this mutation and suggest that it has a substantial founder impact in the Saraiki-derived Jhakar tribe of Pakistan. Based on these findings, we propose creating a molecular diagnostic tool for premarital and prenatal screening of breast cancer-risk families.
References
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[22] Muzammal M, Ahmad S, Ali MZ, Fatima S, Abbas S, Khan J, et al. Whole exome sequencing coupled with in silico functional analysis identified NID1 as a novel candidate gene causing neuro-psychiatric disorder in a Pakistani family. J Natl Sci Found 2024;51. https://doi.org/10.4038 /jnsfsr.v51i4.11256.
[23] Muzammal M, Khan MA, Mohaini M Al, Alsalman AJ, Hawaj MA Al, Farid A. In Silico Analysis of Honeybee Venom Protein Interaction with Wild Type and Mutant (A82V + P375S) Ebola Virus Spike Protein. Biologics 2022;2. https://doi.org/10.3390/biologics2010003.
[24] Muzammal M, Firoz A, Ali HM, Farid A, Khan MA, Hakeem KR. Lumateperone Interact with S-Protein of Ebola Virus and TIM-1 of Human Cell Membrane: Insights from Computational Studies. Applied Sciences (Switzerland) 2022;12. https://doi.org/10.3390/app12178820.
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[26] Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER suite: Protein structure and function prediction. Nat Methods 2014;12. https://doi.org/10.1038/nmeth.3213.
[27] Muzammal M, Ali MZ, Brugger B, Blatterer J, Ahmad S, Taj S, et al. A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37. https://doi.org/10.1007/s11011-021-00832-2.
[28] Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera - A visualization system for exploratory research and analysis. J Comput Chem 2004;25. https://doi.org/10.1002/jcc.20084.
[29] Kozakov D, Hall DR, Xia B, Porter KA, Padhorny D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc 2017;12. https://doi.org/10.1038/nprot.2016.169.
[30] N. Alhashem Y, Farid A, Al Mohaini M, Muzammal M, Hashim Khan M, Dadrasnia A, et al. Protein Isolation and Separation Techniques of Pasteurella multocidavia One- and Two-Dimen-Sional Gel Electrophoresis. Int J Curr Res Rev 2022;14. https://doi.org/10.31782 /ijcrr.2022.141208.
[31] Al Hawaj MA, Farid A, Al Mohaini M, J. Alsalman A, Muzammal M, Hashim Khan M, et al. Biosurfactant Screening and Antibiotic Analysis of Bacillus salmalaya. Int J Curr Res Rev 2022;14. https://doi.org/10.31782/ijcrr.2022.141209.
[32] Ali MZ, Farid A, Ahmad S, Muzammal M, Mohaini M Al, Alsalman AJ, et al. In Silico Analysis Identified Putative Pathogenic Missense nsSNPs in Human SLITRK1 Gene. Genes (Basel) 2022;13. https://doi.org/10.3390/genes13040672.
[33] Abid R, Ghazanfar S, Farid A, Sulaman SM, Idrees M, Amen RA, et al. Pharmacological Properties of 4′, 5, 7‐Trihydroxyflavone (Apigenin) and Its Impact on Cell Signaling Pathways. Molecules 2022;27. https://doi.org/10.3390/molecules27134304.
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Jul 25, 2024
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How to Cite
Muhammad Saifullah, Aiman Saeed Khan, Majida Khan, Zuheeb Ahmed, Kainat Fatima, Zia Ur Rehman, & Jabbar KHAN. (2024). EXOME SEQUENCING COUPLED WITH IN SILICO FUNCTIONAL ANALYSIS IN CONSANGUINEOUS PAKISTANI FAMILIES INHERITING BREAST CANCER DETERMINED THE FOUNDER EFFECT OF THE MUTATION C.1961DUPA (P.TYR655VALFS18*) IN THE BRCA1 GENE. Journal of Population Therapeutics and Clinical Pharmacology, 31(7), 2249-2259. https://doi.org/10.53555/56bmpz19
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Author Biographies
Muhammad Saifullah
Institute of Biological Sciences, Gomal University, Dera Ismail Khan 29050, Khyber Pakhtunkhwa, Pakistan
Aiman Saeed Khan
Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan 29050, Khyber Pakhtunkhwa, Pakistan
Majida Khan
Department of Obstetrics and Gynecology, Institute of LUMHS Jamshoro, Sindh, Pakistan
Zuheeb Ahmed
Department of Pharmacy, Shah Abdul Latif University, Khairpur, Sindh, Pakistan
Kainat Fatima
Department of Pharmacy, Shah Abdul Latif University, Khairpur, Sindh, Pakistan
Zia Ur Rehman
Institute of Biological Sciences, Gomal University, Dera Ismail Khan 29050, Khyber Pakhtunkhwa, Pakistan
Jabbar KHAN
Professor Institute of Biological Sciences, Gomal University, Dera Ismail Khan 29050, Khyber Pakhtunkhwa, Pakistan
How to Cite
Muhammad Saifullah, Aiman Saeed Khan, Majida Khan, Zuheeb Ahmed, Kainat Fatima, Zia Ur Rehman, & Jabbar KHAN. (2024). EXOME SEQUENCING COUPLED WITH IN SILICO FUNCTIONAL ANALYSIS IN CONSANGUINEOUS PAKISTANI FAMILIES INHERITING BREAST CANCER DETERMINED THE FOUNDER EFFECT OF THE MUTATION C.1961DUPA (P.TYR655VALFS18*) IN THE BRCA1 GENE. Journal of Population Therapeutics and Clinical Pharmacology, 31(7), 2249-2259. https://doi.org/10.53555/56bmpz19
