In Silico Analysis Revealed Five Novel High-Risk Single-Nucleotide Polymorphisms (rs200384291, rs201163886, rs193141883, rs201139487, and rs201723157) in ELANE Gene Causing Autosomal Dominant Severe Congenital Neutropenia 1 and Cyclic Hematopoiesis

Abstract

Single-nucleotide polymorphisms in the ELANE (Elastase, Neutrophil Expressed) gene are associated with severe congenital neutropenia, while the ELANE gene provides instructions for making a protein called neutrophil elastase. We identified disease susceptibility single-nucleotide polymorphisms (SNPs) in the ELANE gene using several computational tools. We used cutting-edge computational techniques to investigate the effects of ELANE mutations on the sequence and structure of the protein. Our study suggested that eight nsSNPs (rs28931611, rs57246956, rs137854448, rs193141883, rs201723157, rs201139487, rs137854451, and rs200384291) are the most deleterious in ELANE gene and disturb protein structure and function. The mutants F218L, R34W, G203S, R193W, and T175M have not yet been identified in patients suffering from SCN and cyclic hematopoiesis, while C71Y, P139R, C151Y, G214R, and G203C reported in our study are already associated with both of the disorders. These mutations are shown to destabilize structure and disrupt ELANE protein activation, splicing, and folding and might diminish trypsin-like serine protease efficiency. Prediction of posttranslation modifications highlighted the significance of deleterious nsSNPs because some of nsSNPs affect potential phosphorylation sites. Gene-gene interactions showed the relation of ELANE with other genes depicting its importance in numerous pathways and coexpressions. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking. This research sheds light on how ELANE failure upon mutation results in disease progression, including congenital neutropenia, and validation of these novel predicted nsSNPs is required through the wet lab.

Case Report: Characterization of known (c.607G>C) and novel (c.416C>G) ELANE mutations in two Mexican families with congenital neutropenia

“…The clinical expression of CN (SCN or CyN), depending on the mutation, is homogeneous or variable, suggesting different pathogenic mechanisms ( 36 ). Previous in silico analyses showed a potentially high risk of altered protein structure and function for c.607G>C (rs201139487) and c.416C>G (rs137854448) ( 37 ) located in the same codon of SNV reported here for the first time. Additionally, Shinwari et al.…”

“…Additionally, Shinwari et al. ( 37 ) reported that these SNVs were related to SCN and CyN ( 24 , 25 ).…”

Botulinum toxin type A ameliorates rat dorsal root ganglia neuron pyroptosis in postherpetic neuralgia by upregulating cathelicidin antimicrobial peptide to inhibit neutrophil elastase

“…Moreover, researches had shown that ELINE is coexpressed with multiple genes (Zhao et al., 2023). However, the ELINE gene is predicted to have 20 single nucleotide polymorphisms (nsSNPs) as destructive, which can affect and impair the normal function of other interacting genes (Shinwari et al., 2022). The current study showed that CAMP could interact with ELANE and ELANE knockdown offset the effect of CAMP silencing on viability and NLRP3 inflammasome‐mediated pyroptosis as well as inflammatory responses in DRG neurons.…”