Dataset Information

Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction.

ABSTRACT: Calcium (Ca²⁺) 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 Ca_V channels. Here we describe a mutation in the L-type Ca²⁺ channel Ca_V1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. Ca_V1.4-deficient mice exhibited an expansion of central and effector memory T lymphocytes, and an upregulation of inhibitory receptors on several T cell subsets. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Functionally, T lymphocytes exhibited a reduced store-operated Ca²⁺ flux compared to wild-type controls. Finally, modifying environmental conditions by herpes virus infection exacerbated the dysfunctional immune phenotype of the Ca_V1.4-deficient mice. This is the first example where the mutation of a Ca_V channel leads to T lymphocyte dysfunction, including the upregulation of several inhibitory receptors, hallmarks of T cell exhaustion, and establishes the physiological importance of Ca_V channel signaling in maintaining a nimble immune system.

SUBMITTER: Fenninger F

PROVIDER: S-EPMC6833481 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction.

Fenninger Franz F Han Jeffrey J Stanwood Shawna R SR Nohara Lilian L LL Arora Hitesh H Choi Kyung Bok KB Munro Lonna L Pfeifer Cheryl G CG Shanina Iryna I Horwitz Marc S MS Jefferies Wilfred A WA

Frontiers in immunology 20191029

Calcium (Ca2+) 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 a mutation in the L-type Ca2+ channel CaV1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. CaV1.4-deficient mice exhibited an expansion of central and e ...[more]

PMID: 31736943

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Project description:Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit.The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)?(2)?-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Ca(v)1.2?1 and Ca(v)?(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Ca(v)?(2)?-1 subunit strongly reduced the I(Ba) by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Ca(v)?(2)?-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Ca(v)?(2)?-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Ca(v)1.2?1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant.In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.

Dataset Information

Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction.

Publications

Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction.

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