A Review of Genetic and Physiological Disease Mechanisms Associated With Cav1 Channels: Implications for Incomplete Congenital Stationary Night Blindness Treatment.

Tal T Sadeh,Forbes Manson,Graeme C Black

doi:10.3389/fgene.2021.637780

Abstract

Calcium channels are crucial to a number of cellular functions. The high voltage-gated calcium channel family comprise four heteromeric channels (Cav1.1-1.4) that function in a similar manner, but that have distinct expression profiles. Three of the pore-forming α1 subunits are located on autosomes and the forth on the X chromosome, which has consequences for the type of pathogenic mutation and the disease mechanism associated with each gene. Mutations in this family of channels are associated with malignant hyperthermia (Cav1.1), various QT syndromes (Cav1.2), deafness (Cav1.3), and incomplete congenital stationary night blindness (iCSNB; Cav1.4). In this study we performed a bioinformatic analysis on reported mutations in all four Cav α1 subunits and correlated these with variant frequency in the general population, phenotype and the effect on channel conductance to produce a comprehensive composite Cav1 mutation analysis. We describe regions of mutation clustering, identify conserved residues that are mutated in multiple family members and regions likely to cause a loss- or gain-of-function in Cav1.4. Our research highlights that therapeutic treatments for each of the Cav1 channels will have to consider channel-specific mechanisms, especially for the treatment of X-linked iCSNB.

Highlights

Voltage-gated calcium channels perform multiple functions including signaling, hormone and neurotransmitter secretion, muscle contraction, and gene expression (Catterall et al, 2005)
Cav1.1-1.3 channels are encoded by autosomal genes; the Cav1.4 channel is encoded by the X-linked CACNA1F gene
Each of these S5–S6 loops contains a conserved glutamate residue that forms a negatively charged ring that functions as the ion-selectivity filter (Yang et al, 1993). Their conserved properties enable the four Cav1 channels to function in a similar fashion, albeit in different temporo-spatial circumstances, for calcium homeostasis (Zamponi et al, 2015): The α1 subunit of Cav1.1 is encoded by the CACNA1S gene located on chromosome 1q32.1 and is exclusively expressed in skeletal muscle (Catterall et al, 2005)

Summary

Introduction

Voltage-gated calcium channels perform multiple functions including signaling, hormone and neurotransmitter secretion, muscle contraction, and gene expression (Catterall et al, 2005). The S5 and S6 segments form the pore, which is lined by the S5–S6 loops Each of these S5–S6 loops contains a conserved glutamate residue that forms a negatively charged ring that functions as the ion-selectivity filter (Yang et al, 1993). Their conserved properties enable the four Cav channels to function in a similar fashion, albeit in different temporo-spatial circumstances, for calcium homeostasis (Zamponi et al, 2015): The α1 subunit of Cav1.1 is encoded by the CACNA1S gene located on chromosome 1q32.1 and is exclusively expressed in skeletal muscle (Catterall et al, 2005). The channels’ unique tissue expression profiles are reflected in their different voltage-dependencies i.e., they activate and inactivate at different voltages

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