The disruptive influence of the Ala218Val variant on the ENG protein

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that interferes with the formation of arteries. The ENG gene encodes for the protein endoglin which is used to properly develop and remodel arteries. The removal of endoglin forms telangiectasias that cause bleeding from the nose and vital organs. This study investigates the impact of one of the many variants of uncertain significance of ENG associated with HHT. The missense swap of alanine for valine at position 218 (Ala218Val) was characterized through computational metrics from in silico pathogenicity prediction tools, conservation analysis, and molecular dynamics simulation (MDS). The structural residue is highly conserved over multiple species and buried. The missense swap resulted in a difference in movement from the wild type according to MDS in a simulated aqueous environment. Therefore, it is predicted to be likely pathogenic.

Figure 1. Characterization of ENG Variant ALA218Val

A) Comparison of prediction for Ala218Val to the pathogenicity threshold for each computational tool. All resulting scores except SIFT were above the threshold (Abzhubei et al., 2013; Llorca et al., 2007; Ng & Henikoff, 2001). B) Conservation ranking of the Ala218Val residue based on ConSurf, predicted the variant to be a structural residue - indicated by the s - that is highly conserved and buried - indicated by the b (Landau et al., 2005). C) Molecular dynamics simulations run on the native type and on the variant Ala218Val show the root mean squared deviations (RMSD), calculated over 20 nanoseconds in a simulated aqueous environment. D) The RMSF of the wild-type and mutation of Ala218Val show the fluctuation by amino acid position. An arrow points to position 218 of the protein. A visual difference is observed (Land & Humble, 2018).