Mutation of an L-Type Calcium Channel Gene Leads to a Novel Human Primary Cellular Immunodeficiency

Abstract

Human primary immunodeficiencies are inherited diseases that can provide valuable insight into the immune system. Calcium is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and CaV channels. Here we describe three CaV1.4-deficient siblings presenting with X-linked incomplete congenital stationary night blindness as well as an immune phenotype characterized by several recurrent infections. The subjects uniformly exhibited an expansion of central and effector memory T lymphocytes, and evidence of T lymphocytes exhaustion with corresponding upregulation of inhibitory receptors. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. This is the first example where the mutation of any CaV channel causes a primary immunodeficiency in humans and establishes the physiological importance of CaV channels in the human immune system.