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Structure analysis of deleterious nsSNPs in human PALB2 protein for functional inference

Noshin Nawar1, Anik Paul1, Hamida Nooreen Mahmood1

  • 1Clinical Biochemistry and Translational Medicine Laboratory, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh.

Bioinformation
|June 7, 2021
PubMed

Insights

This study analyzes single nucleotide polymorphisms (SNPs) in the PALB2 gene, identifying damaging variants that may increase breast and ovarian cancer risk. These findings highlight potential disease-associated SNPs for further clinical investigation.

Area of Science:

  • Genetics
  • Molecular Biology
  • Bioinformatics

Background:

  • Partner and Localizer of BRCA2 (PALB2) is crucial for DNA repair and acts as a tumor suppressor.
  • Mutations in PALB2 are linked to increased breast and ovarian cancer susceptibility.
  • Comprehensive characterization of PALB2 single nucleotide polymorphisms (SNPs) is lacking.

Purpose of the Study:

  • To conduct a comprehensive in silico analysis of coding and non-coding SNPs in the PALB2 gene.
  • To identify functionally significant and structurally damaging PALB2 variants.
  • To investigate the impact of non-coding SNPs on miRNA target sites.

Main Methods:

  • Retrieved 1455 non-synonymous SNPs (nsSNPs) from dbSNP.
  • Utilized multiple in silico tools (SIFT, PROVEAN, PolyPhen, etc.) for SNP characterization.
  • Performed structural analysis, protein stability assessment, and 3D modeling (SWISS Model) for top nsSNPs.
  • Analyzed 3' UTR SNPs for altered miRNA binding sites.

Main Results:

  • Identified 28 functionally important nsSNPs, with 16 selected for further structural analysis.
  • Located the most deleterious nsSNPs within the PALB2 WD40 domain.
  • Modeled 16 mutant structures, identifying three highly damaging variants (rs78179744, rs180177123, rs45525135).
  • Analyzed non-coding SNPs for potential disruption of miRNA targeting.

Conclusions:

  • This study provides a comprehensive list of damaging coding and non-coding PALB2 SNPs.
  • Identified variants hold potential for disease association, particularly in breast and ovarian cancers.
  • Further genetic association studies are recommended to confirm clinical significance.
Keywords:
PALB2UTRin silico characterizationnsSNP

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