Protein Subdomain Enrichment of NUP155 Variants Identify a Novel Predicted Pathogenic Hotspot

Abstract

Functional variants in nuclear envelope genes are implicated as underlying causes of cardiopathology. To examine the potential association of single nucleotide variants of nucleoporin genes with cardiac disease, we employed a prognostic scoring approach to investigate variants of NUP155, a nucleoporin gene clinically linked with atrial fibrillation. Here we implemented bioinformatic profiling and predictive scoring, based on the gnomAD, National Heart Lung and Blood Institute-Exome Sequencing Project (NHLBI-ESP) Exome Variant Server, and dbNSFP databases to identify rare single nucleotide variants (SNVs) of NUP155 potentially associated with cardiopathology. This predictive scoring revealed 24 SNVs of NUP155 as potentially cardiopathogenic variants located primarily in the N-terminal crescent-shaped domain of NUP155. In addition, a predicted NUP155 R672G variant prioritized in our study was mapped to a region within the alpha helical stack of the crescent domain of NUP155. Bioinformatic analysis of inferred protein-protein interactions of NUP155 revealed over representation of top functions related to molecular transport, RNA trafficking, and RNA post-transcriptional modification. Topology analysis revealed prioritized hubs critical for maintaining network integrity and informational flow that included FN1, SIRT7, and CUL7 with nodal enrichment of RNA helicases in the topmost enriched subnetwork. Furthermore, integration of the top 5 subnetworks to capture network topology of an expanded framework revealed that FN1 maintained its hub status, with elevation of EED, CUL3, and EFTUD2. This is the first study to report novel discovery of a NUP155 subdomain hotspot that enriches for allelic variants of NUP155 predicted to be clinically damaging, and supports a role for RNA metabolism in cardiac disease and development.

Vascular Inflammation as a Therapeutic Target in COVID-19 “Long Haulers”: HIITing the Spot?

“…In terms of the concerns of increasing the risk of adverse cardiovascular outcomes by HIIT in COVID-19 survivors, other reports suggest otherwise ( 48 ). Hence, a recent, admittedly small retrospective study of 28 discharged COVID-19 survivors reported that rehabilitation triggered by HIIT, with endurance training at the maximum tolerated exercise load was both safe and feasible ( 49 ).…”

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…The global co-and post-transcriptional mechanisms implicated in cardiac fibrosis are not well established, however, emerging studies are geared at extracting the subtle communications to identify intersection points between the cellular stress regulating pathways, regulatory non-coding RNAs, RNA metabolism intermediates/mediators and cardiac RNA binding proteins (RBFox, HuR, MBNL2, PUM2, QKI, CELF1, MBNL1, PTBP1) in context of cardiac diseases including fibrosis [66,[112][113][114][115][116][117][118][119][120]. A recent study implicated NUP155 subdomain hotspot with enriched allelic variants of the gene that suggests important role of RNA metabolism in cardiac disease and development [121].…”

“…Immunostimulatory RNAs (like double stranded RNAs) generated through deregulated RNA processing pathways along with RNA binding proteins of RNA helicase (RNA sensors) family are emerging as important components of immune response pathways during sterile inflammation that involves DAMP sensing [15,16]. Mitochondrial quality control pathways intersecting with the endosomal compartments and lysosomes are recently reported to favor generation and release of mitochondrial-derived vesicles in former condition [143], further offering discernible biologically stable lipid vesicles that may help investigate how secreted cargos can impact tissue repair and homeostasis or trigger fibrosis, and can be extended to establishment of liquid biopsies for studying the progression of fibrotic diseases or alternatively these vesicles may serve as therapeutic tools like exosome-derived non coding RNAs [121,125,127,128,138,139,141,144] circulating microRNAs (miRNAs) and tissue resident miRNAs play paradoxical role both as anti-fibrotic [145][146][147][148] and profibrotic [149][150][151].…”

Cryo-EM structure of human Nup155 reveals the biochemical basis for atrial fibrillation linked genetic mutation R391H

“…(Andersen et al, 2020). A recent study revealed that the N-terminal β-propeller domain is the hotspot, where most of the clinically linked allelic variants of NUP155 (24 variants) are clustered and present around R391H and L503F mutations(Leonard et al, 2020;Zhang et al, 2016Zhang et al, , 2008). However, it was not clear how this β-propeller domain is affected by these variants.…”