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UBC Theses and Dissertations

Mutation of an L-type calcium channel gene leads to a novel primary cellular immunodeficiency in mice and humans Fenninger, Franz


Human primary immunodeficiencies are inherited diseases that can provide valuable insight into our immune system. Calcium (Ca²⁺) is a vital secondary messenger in T cells that regulates a vast array of important events including maturation, homeostasis, activation, and apoptosis. The proper orchestration of Ca²⁺ signalling is essential to prevent immune related diseases. Upon antigen binding to the T cell receptor, extracellular Ca²⁺ enters the cell through CRAC, TRP and CaV channels. Here we describe a mutation in the L-type Ca²⁺ channel CaV1.4 leading to a novel immunological disorder. Three CaV1.4-deficient siblings presented with X-linked incomplete congenital stationary night blindness as well as recurrent infections, autoimmunity and pro-inflammatory cytokine production. The subjects uniformly exhibited a T cell memory phenotype and T cell exhaustion as well as chronic activation of their B cells. Moreover, their T cells but not B cells exhibited a reduced Ca²⁺ flux, compared to healthy control donors. This is the first example where the mutation of any CaV channel causes a primary immunodeficiency in humans and establishes their physiological importance in the immune system. In parallel, we detected a remarkably similar phenotype in a CaV1.4-deficient mouse model. In a separate set of experiments, a commercially available C57BL/6 mouse strain harbouring an undescribed mutation in Dock2, was introduced into our breeding stock resulting in some mice with a double deficiency of DOCK2 and CaV1.4. This provided the opportunity to assess the compound phenotype. We found that the double-deficient mouse model exhibited severe splenic cytopenia as well as chronic B cell activation but impaired BCR-induced activation / Ca²⁺ mobilization.

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