Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies.

Jörg Striessnig

doi:10.3389/fnsyn.2021.634760

Abstract

This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.

Highlights

Decreasing cost for next-generation sequencing (NGS) has allowed to diagnose pathogenic mutations in an increasing number of patients affected by genetic diseases
Pathogenic variants directly hitting the negative charges forming the Ca2+ selectivity filter are rare but have been reported for Cav1.2 (E1135K) associated with Long QT Syndrome 8 (LQT8) and Cav2.1 associated with a Spinocerebellar Ataxia Type 6 (SCA6) phenotype
This can create a channel population permeable for monovalent cations with Na+-mediated inward currents and K+-mediated outward currents. It can explain the prolongation of the cardiac action potential in cardiomyocytelike cells derived from human induced pluripotent stem cells expressing the E1135K LQT8 variant (Ye et al, 2019)

Summary

Jörg Striessnig*

This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. In contrast to likely gene disrupting mutations these can cause a channel lossof-function but can induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could be of therapeutic interest

INTRODUCTION

Channel Loss of Function Mutations

Pathogenic Gating Pore Currents

Other Mechanisms

Findings

IMPLICATIONS FOR THERAPY