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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Computational analyses and prediction of guanylin deleterious SNPs
William F Porto1, Octávio L Franco2, Sérgio A Alencar3
1Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília-DF, Brazil.
Abstract:
Human guanylin, coded by the GUCA2A gene, is a member of a peptide family that activates intestinal membrane guanylate cyclase, regulating electrolyte and water transport in intestinal and renal epithelia. Deregulation of guanylin peptide activity has been associated with colon adenocarcinoma, adenoma and intestinal polyps. Besides, it is known that mutations on guanylin receptors could be involved in meconium ileus. However, there are no previous works regarding the alterations driven by single nucleotide polymorphisms in guanylin peptides. A comprehensive in silico analysis of missense SNPs present in the GUCA2A gene was performed taking into account 16 prediction tools in order to select the deleterious variations for further evaluation by molecular dynamics simulations (50 ns). Molecular dynamics data suggest that the three out of five variants (Cys104Arg, Cys112Ser and Cys115Tyr) have undergone structural modifications in terms of flexibility, volume and/or solvation. In addition, two nonsense SNPs were identified, both preventing the formation of disulfide bonds and resulting in the synthesis of truncated proteins. In summary the structural analysis of missense SNPs is important to decrease the number of potential mutations to be in vitro evaluated for associating them with some genetic diseases. In addition, data reported here could lead to a better understanding of structural and functional aspects of guanylin peptides.
Insights
Single nucleotide polymorphisms (SNPs) in the human guanylin (GUCA2A) gene can alter protein structure and function. This study identifies specific deleterious missense and nonsense SNPs, aiding in genetic disease association studies.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Human guanylin (GUCA2A) regulates electrolyte and water transport.
- Guanylin peptide deregulation is linked to colon cancer and intestinal polyps.
- Mutations in guanylin receptors are implicated in meconium ileus.
Purpose of the Study:
- To investigate the structural and functional impact of single nucleotide polymorphisms (SNPs) in the GUCA2A gene.
- To identify deleterious missense and nonsense SNPs in guanylin peptides using in silico methods.
Main Methods:
- Comprehensive in silico analysis of missense SNPs in the GUCA2A gene using 16 prediction tools.
- Molecular dynamics simulations (50 ns) to evaluate the structural effects of selected deleterious variants.
- Identification of nonsense SNPs and their predicted impact on protein synthesis.
Main Results:
- Three missense variants (Cys104Arg, Cys112Ser, Cys115Tyr) showed significant structural modifications (flexibility, volume, solvation) in molecular dynamics simulations.
- Two nonsense SNPs were identified, predicted to cause truncated proteins and prevent disulfide bond formation.
- The study successfully filtered potentially deleterious SNPs for further in vitro evaluation.
Conclusions:
- In silico structural analysis of missense SNPs is crucial for prioritizing mutations for experimental validation.
- Identified GUCA2A SNPs provide insights into structural and functional aspects of guanylin peptides.
- This research contributes to understanding the genetic basis of diseases associated with guanylin peptide dysregulation.
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