Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

Abstract

Regulators of G protein signaling (RGS) proteins modulate the physiologic actions of many neurotransmitters, hormones, and other signaling molecules. Human RGS proteins comprise a family of 20 canonical proteins that bind directly to G protein-coupled receptors/G protein complexes to limit the lifetime of their signaling events, which regulate all aspects of cell and organ physiology. Genetic variations account for diverse human traits and individual predispositions to disease. RGS proteins contribute to many complex polygenic human traits and pathologies such as hypertension, atherosclerosis, schizophrenia, depression, addiction, cancers, and many others. Recent analysis indicates that most human diseases are due to extremely rare genetic variants. In this study, we summarize physiologic roles for RGS proteins and links to human diseases/traits and report rare variants found within each human RGS protein exome sequence derived from global population studies. Each RGS sequence is analyzed using recently described bioinformatics and proteomic tools for measures of missense tolerance ratio paired with combined annotation-dependent depletion scores, and protein post-translational modification (PTM) alignment cluster analysis. We highlight selected variants within the well-studied RGS domain that likely disrupt RGS protein functions and provide comprehensive variant and PTM data for each RGS protein for future study. We propose that rare variants in functionally sensitive regions of RGS proteins confer profound change-of-function phenotypes that may contribute, in newly appreciated ways, to complex human diseases and/or traits. This information provides investigators with a valuable database to explore variation in RGS protein function, and for targeting RGS proteins as future therapeutic targets.

Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons

“…This genetic diversity is not captured by canonical reference protein sequences and, despite selective pressure, missense variations within exonic coding regions frequently arise in modular protein domains that can have profound impact on protein functions. While many studies focus on monogenetic variations in the context of severe diseases and phenotypes, rare variants may actually play a more important role in susceptibility, particularly for complex diseases (1)(2)(3)(4)(5)(6)(7)(8). Many of these rare variants are predicted to alter protein function which could impact linked physiology.…”

Genetic variants disrupt human RGS14 binding to NHERF1 and regulation of NPT2A-mediated phosphate transport

“…The RGS14 gene on human chromosome 5 is adjacent to SLC34A1 that encodes the NPT2A sodiumphosphate cotransporter. Coding mutations have been identified (20) in the human RGS14 PDZ-binding motif, as we reported (21), though the impact of these variants on RGS14 function is unknown.…”

“…Several rare coding mutations have been noted in the PDZ-binding motif of human RGS14 (21). These mutations are situated at residues D563 and A565, corresponding to positions -1 and -3 of the PDZ ligand.…”

Heterotrimeric G-protein subunit Gα i2 contributes to agonist-sensitive apoptosis and degranulation in murine platelets

“…; Squires et al. ). In platelets, fundamental elements of the hemostasis machinery, a wide array of cell surface receptors coupled to G proteins mediate their activation (Offermanns ).…”

“…Heterotrimeric G proteins are coupled to plasma membrane receptors and participate in the regulation of a wide range of cellular functions such as migration, differentiation, proliferation, ion channel activity, and apoptosis (Hilger et al 2018;Squires et al 2018). In platelets, fundamental elements of the hemostasis machinery, a wide array of cell surface receptors coupled to G proteins mediate their activation (Offermanns 2006).…”