Loss of function mutation in the P2X7, a ligand-gated ion channel gene associated with hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited heart failure condition, mostly found to have genetic abnormalities, and is a leading cause of sudden death in young adults. Whole exome sequencing should be given consideration as a molecular diagnostic tool to identify disease-causing mutation/s. In this study, a HCM family with multiple affected members having history of sudden death were subjected to exome sequencing along with unaffected members. Quality passed variants obtained were filtered for rarity (MAF > 0.5%), evolutionary conservation, pathogenic prediction, and segregation in affected members after removing shared variants present in unaffected members. Only one non-synonymous mutation (p. Glu186Lys or E186K) in exon 6 of P2X7 gene segregated in HCM-affected individuals which was absent in unaffected family members and 100 clinically evaluated controls. The site of the mutation is highly conserved and led to complete loss of function which is in close vicinity to ATPbinding site-forming residues, affecting ATP binding, channel gating, or both. Mutations in candidate genes which were not segregated define clinical heterogeneity within affected members. P2X7 gene is highly expressed in the heart and shows direct interaction with major candidate genes for HCM. Our results reveal a significant putative HCM causative gene, P2X7, for the first time and show that germ-line mutations in P2X7 may cause a defective phenotype, suggesting purinergic receptor involvement in heart failure mediated through arrhythmias which need further investigations to be targeted for therapeutic interventions.

Mitochondrial P2X7 Receptor Localization Modulates Energy Metabolism Enhancing Physical Performance

“…Involvement of the P2X7R in heart dysfunction is at present very speculative. A loss-of-function mutation in the P2RX7 gene (556C>A) has been recently found to associate with hypertrophic cardiomyopathy in a family from India, 54 but another study found no association between two P2RX7 SNPs, the gain of function 489C>T and the loss-of-function 1513A>C, and acute heart failure in a geriatric population. 55 Despite this contrasting evidence, our study highlights an as yet un-described function of the P2X7R in the regulation of mitochondrial metabolism and points to a potentially relevant role in cardiac function and physical fitness.…”

A genetic correlation and bivariate genome-wide association study of grip strength and depression

“…P2RX7 is associated with the inflammatory response and neuroimmune mechanisms of depression and neurodegenerative diseases [ 54 , 55 ]. This gene can also affect calcium channels [ 56 , 57 ] and is associated with bone and joint diseases [ 58 ]. Therefore, P2RX7 may affect muscle strength.…”

The P2X7 receptor localizes to the mitochondria, modulates mitochondrial energy metabolism and enhances physical performance

“…Involvement of the P2X7R in heart dysfunction is at present very speculative. A loss-of-function mutation in the P2RX7 gene (556C>A) has been recently found to associate with hypertrophic cardiomyopathy in a family from India (Biswas et al 2019), but another study found no association between two P2RX7 SNPs, the gain of function 489C>T and the loss-of-function 1513A>C, and acute heart failure in a geriatric population (Pasqualetti et al 2017). Despite this contrasting evidence, our study highlights an as yet un-described function of the P2X7R in the regulation of mitochondrial metabolism and points to a potentially relevant role in cardiac function and physical fitness.…”