Prediction of the impact of coding missense and nonsense single nucleotide polymorphisms on HD5 and HBD1 antibacterial activity against <i>Escherichia coli</i>

Porto, William F.; Nolasco, Diego O.; Pires, Állan S.; Pereira, Rinaldo Wellerson; Franco, Octávio Luiz; Alencar, Sérgio Amorim de

doi:10.1002/bip.22866

Cited by 15 publications

(9 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This stop codon truncates the mature beta defensin 1 peptide sequence after four amino acids, so no active peptide is made (Porto et al. ). Additionally, the translated truncated N‐terminal peptide could serve as a dominant negative, competing for the intact signal peptide or processing protease of intact beta‐defensin 1 peptide encoded by the other DEFB1 allele.…”

Section: Resultsmentioning

confidence: 99%

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

Modi

Teves

Pearson

et al. 2017

Molec Gen & Gen Med

View full text Add to dashboard Cite

BackgroundTwin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM.MethodsWe carried out whole exome sequencing (WES) of genomic DNA from neonates born of African‐American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies (N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes. Targeted genotyping of mutations in the candidates discovered by WES was conducted on an additional 188 PPROM cases and 175 controls.ResultsWe identified rare heterozygous nonsense and frameshift mutations in several of the candidate genes, including CARD6, CARD8, DEFB1, FUT2, MBL2, NLP10, NLRP12, and NOD2. We discovered that some mutations (CARD6, DEFB1, FUT2, MBL2, NLRP10, NOD2) were present only in PPROM cases.ConclusionsWe conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in African‐Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products.

show abstract

Section: Resultsmentioning

confidence: 99%

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

Modi

Teves

Pearson

et al. 2017

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…We verified by Sanger sequencing that the minor allele of rs5743490 that we detected encoded a stop codon [ 9 ]. This DEFB1 nonsense variant truncates the DEFB1 protein 4 amino acids into the mature peptide amino acid sequence so that no functional DEFB1 would be made [ 10 ]. However, the mutant protein, if expressed, could have dominant negative activity by preventing proteolytic processing of the un-mutated pro-peptide encoded by the normal allele.…”

Section: Resultsmentioning

confidence: 99%

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

et al. 2018

View full text Add to dashboard Cite

BackgroundPreterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.MethodsWe developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.ResultsWe describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.ConclusionsOur findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0696-4) contains supplementary material, which is available to authorized users.

show abstract

“…Besides, combinatorial analysis of different algorithms makes the predicted effects of particular mutations more accurate. Moreover, refined analysis, such as molecular dynamics simulation enables precise evaluation of changes in protein structure, physicochemical properties, and interactions in a simulated environment [28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

Lira

Ahammad²

2021

Preprint

View full text Add to dashboard Cite

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein-ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

show abstract

Prediction of the impact of coding missense and nonsense single nucleotide polymorphisms on HD5 and HBD1 antibacterial activity against Escherichia coli

Cited by 15 publications

References 84 publications

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

Contact Info

Product

Resources

About