In silico study of missense variants of FANCA, FANCC and FANCG genes reveals high risk deleterious alleles predisposing to Fanconi anemia pathogenesis

Muhammad Shahid; Ahmad Azfaralariff; Muhammad Zubair; Ahmed Abdulkareem Najm; Nahid Khalili; Douglas Law; Sabika Firasat; Shazrul Fazry

doi:10.1016/j.gene.2021.146104

In silico study of missense variants of FANCA, FANCC and FANCG genes reveals high risk deleterious alleles predisposing to Fanconi anemia pathogenesis

Gene. 2022 Feb 20:812:146104. doi: 10.1016/j.gene.2021.146104. Epub 2021 Dec 2.

Authors

Muhammad Shahid¹, Ahmad Azfaralariff², Muhammad Zubair³, Ahmed Abdulkareem Najm¹, Nahid Khalili¹, Douglas Law⁴, Sabika Firasat⁵, Shazrul Fazry⁶

Affiliations

¹ Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.
² Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia.
³ Department of Wildlife and Ecology, University of Veterinary and Animal Sciences, Pattoki Campus, Pakistan.
⁴ Faculty of Health and Life Sciences, Inti International University, Persiaran Perdana BBN Putra Nilai, 71800 Nilai, Negeri Sembilan.
⁵ Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, 45320 Islamabad, Pakistan.
⁶ Department of Food Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia; ZACH Biotech Depot Private Limited, Cheras, 43300, Selangor, Malaysia; Tasik Chini Research Center, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, Malaysia. Electronic address: shazrul@ukm.edu.my.

PMID: 34864095
DOI: 10.1016/j.gene.2021.146104

Abstract

Among the 22 Fanconi anemia (FA) reported genes, 90% of mutational spectra were found in three genes, namely FANCA (64%), FANCC (12%) and FANCG (8%). Therefore, this study aimed to identify the high-risk deleterious variants in three selected genes (FANCA, FANCC, and FANCG) through various computational approaches. The missense variant datasets retrieved from the UCSC genome browser were analyzed for their pathogenicity, stability, and phylogenetic conservancy. A total of 23 alterations, of which 16 in FANCA, 6 in FANCC and one variant in FANCG, were found to be highly deleterious. The native and mutant structures were generated, which demonstrated a profound impact on the respective proteins. Besides, their pathway analysis predicted many other pathways in addition to the Fanconi anemia pathway, homologous recombination, and mismatch repair pathways. Hence, this is the first comprehensive study that can be useful for understanding the genetic signatures in the development of FA.

Keywords: FANCA; FANCC; FANCG; Fanconi anemia; In silico study; Variation analysis.

MeSH terms

Binding Sites
Computational Biology / methods*
Fanconi Anemia / genetics*
Fanconi Anemia Complementation Group A Protein / chemistry
Fanconi Anemia Complementation Group A Protein / genetics*
Fanconi Anemia Complementation Group C Protein / chemistry
Fanconi Anemia Complementation Group C Protein / genetics*
Fanconi Anemia Complementation Group G Protein / chemistry
Fanconi Anemia Complementation Group G Protein / genetics*
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Models, Molecular
Mutation, Missense*
Protein Conformation
Protein Stability

Substances

FANCA protein, human
FANCC protein, human
FANCG protein, human
Fanconi Anemia Complementation Group A Protein
Fanconi Anemia Complementation Group C Protein
Fanconi Anemia Complementation Group G Protein