alexa Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia: Two Novel Mutations and Genotype-Phenotype Correlation
ISSN: 1747-0862

Journal of Molecular and Genetic Medicine
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Research Article

Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia: Two Novel Mutations and Genotype-Phenotype Correlation

Faisal A Al-Allaf1,2,3#, Mohiuddin M Taher3#*, Zainularifeen Abduljaleel3, Mohammad Athar3, Faisal A Ba-hammam3, Munir Abdulla3, Abdellatif Bouazzaoui3, Halah Abalkhail4 and Tarek MA Owaidah4*

1Faculty of Medicine, Department of Medical Genetics, Umm Al-Qura University, Makkah, Saudi Arabia

2Molecular Diagnostics Unit, Department of Laboratory Medicine and Blood Bank, King Abdullah Medical City, Makkah, Saudi Arabia

3Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia

4Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

#Equal first authors

*Corresponding Authors:
Mohiuddin M Taher
Science and Technology Unit
Umm Al-Qura University
Makkah, Saudi Arabia
Tel: 966125501000
E-mail: [email protected]
Tarek M A Owaidah
Pathology and Laboratory Medicine
King Faisal Specialist
Hospital and Research Centre
Riyadh, Saudi Arabia
Tel: 966114647272
E-mail: [email protected]

Received Date: November 18, 2015; Accepted Date: April 26, 2016; Published Date: April 31, 2016

Citation: Al-Allaf FA, Taher MM, Abduljaleel Z, Athar M, Ba-hammam FA, et al.(2016) Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia:Two Novel Mutations and Genotype-Phenotype Correlation. J Mol Genet Med 10:211 doi:10.4172/1747-0862.1000211

Copyright: © 2016 Al-AllaF FA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

 

Abstract

Background: Hemophilia A is an X-linked bleeding disorder caused by mutations in the factor VIII gene (F8C). Molecular testing for the factor VIII gene is difficult due to its large size. More than 1000 different mutations have been described in factor VIII gene. In this study we have investigated the factor VIII gene mutations in Saudi Arabian population. Methods: For genotyping factor VIII cohorts of 110 samples from Saudi Arabian patients undergoing treatment for hemophilia A were collected. All patients were tested for factor VIII coagulant activity on Behring Coagulation System. Genomic DNA was isolated from blood on MagNapure system. Screening for inv-1 was done by multiplex PCR method, and inv-22 was done by ligation (inverse) PCR method. DNA sequencing was performed by Sanger method for all 26 exons of factor VIII gene. PCR products were sequenced on ABI 3500 Genetic analyzer. For molecular simulations we have used softwares such as CHARMM and GROMACS v4.0.527. In order to predict the possible impact of a variation on the function of factor VIII gene the online tools Polyphen 2, and SIFT were used. Results: Out of 110 cases screened, 2 patients were positive (affected) for inv-1 and 15 patients were positive (12 affected and 3 carriers) for inv-22. Out of 32 cases sequenced for coding exons, 2 novel mutations were found, one novel missense mutation c.355G>C, p. (A119P) in exon 3, and another novel frame shift mutation c.6482delC, p.(P2161Lfs*25) in exon 23. Also known mutations such as, c.409 A>C, p. (T137P) in 2 individual patients in exon 4, another known mutation c.1804C>T, p.(R602*) in 1 patient in exon 12 were found. Genotype-phenotype correlations and computer prediction analysis on these novel mutations and the secondary structure analysis of the factor VIII protein were performed, and compared with the predicted native proteins. Conclusions: These novel mutations in factor VIII gene and molecular dynamic simulation results to appropriately predict the deleterious effects of these mutations are presented in this study. In addition, for the native and mutant proteins models, the amino acid residues and its secondary structures were determined. Our In-silico study suggests that these mutations have significant impact on the structure and function of the factor VIII protein.

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