Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine

Sigma-1 receptor (Sigma1R; SIGMAR1), an integral membrane protein of the endoplasmic reticulum and nuclear envelope, has a hydrophobic drug-binding pocket that binds with high affinity to addictive drugs (cocaine, methamphetamine) and therapeutics used to treat a wide spectrum of neurological disorders. Cocaine enhances Sigma1R association with three nuclear lamina proteins (emerin, lamin A/C, BANF1), causing Sigma1R-dependent and emerin-dependent recruitment and transcriptional repression of a gene, MAOB1, involved in dopamine removal from neural synapses. The mechanism of Sigma1R association with emerin and the molecular impact of cocaine on their association are unknown. Mutations in Sigma1R, as a proposed regulator or mis-regulator of the nuclear lamina, have the potential to alter nuclear lamina function in brain or other tissues. We examined the frequency of SIGMAR1 missense alleles among 60,706 unrelated individuals in the ExAC database. We identified two novel SIGMAR1 missense variants of particular interest due to their frequency and potential to impact molecular association with emerin or other nuclear lamina proteins. Variant p.Q2P was widespread in ExAC (overall allele frequency 18.4%) with broad ethnic distribution among non-Finnish Europeans, Africans, South Asians, Latinx (allele frequencies similar to 15% to 23%), and East Asians (similar to 38%). The p.R208W allele was identified in similar to 0.78% of individuals overall with enrichment in Africans, Latinx, and East Asians (similar to 1.9-2.9%). These and other novel Sigma1R variants provide tools for future studies to determine the molecular basis of Sigma1R association with emerin and the mechanism of nuclear lamina misregulation by cocaine and potentially other Sigma1R agonists. Impact statement The Sigma-1 Receptor (Sigma1R; SIGMAR1) binds neuroactive drugs-both therapeutic and addictive-and associates with the nuclear membrane protein emerin and its partners lamin A/C and BANF1 in response to cocaine, through unknown mechanisms. We identified two novel SIGMAR1 missense variants of special interest due to their prevalence in human populations and their potential to perturb Sigma1R function at the nuclear envelope. Despite its importance in physiology and pharmacology, many aspects of Sigma1R including its membrane topology are unclear. Our findings lay the foundation for future molecular studies to understand how Sigma1R associates with emerin, lamin A/C, and BANF1 and manipulates their activity in response to agonist.