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

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.

Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation

“…We selected 10 CACNA1F VUS from local patients via a putative CSNB2 diagnosis ( Table 1 ). As it was shown previously that the connecting loops are the most frequently substituted regions in the Ca v 1 family ( Sadeh et al, 2021 ), we selected two variants in these loops: p.D119Y (identified in a male patient with an electronegative electroretinogram (ERG)) and p.E797V (identified in two unrelated families ( Hove et al, 2016 )). We further chose four variants in the pore-forming domains: p.R290C, p.G674S, p.D1097N, and p.N1434S.…”

“…We further chose four variants in the pore-forming domains: p.R290C, p.G674S, p.D1097N, and p.N1434S. These pore variants are functionally constrained and likely to dysregulate Ca 2+ influx ( Sadeh et al, 2021 ). All four Ca v 1.4 pore variants are novel and were present in male patients that had ERGs consistent with diagnosis of CSNB2; p. R290C was present in four family members and p.N1434S was present in two cousins, all affected with CSNB2 ( Table 1 ).…”

“…Pathogenic variants in CACNA1F , which is highly expressed in the retina, cause X-linked CSNB2, a rare disorder causing visual disability in males. In this context, the interpretation of missense variant pathogenicity across the entire Ca v 1 family remains challenging ( Brunklaus et al, 2014 ; Heyne et al, 2020 ; Indelicato and Boesch, 2021 ; Sadeh et al, 2021 ) and can delay diagnosis and treatment. To this end, we and other researchers have developed informatics tools, including CACNA1F-vp and funNCIon ( Heyne et al, 2020 ; Sallah et al, 2020 ), and in this experimental follow-up study, have undertaken functional studies to examine the efficacy of these tools.…”

“…The mechanisms through which missense mutations act to disrupt each Ca v 1 channel vary and include both gain of function (GoF) and loss of function (LoF) ( Sadeh et al, 2021 ). Across the spectrum of these disorders, however, it remains unclear whether the phenotypes arise from decreased protein expression, protein instability, or changes to channel kinetics ( Hoda et al, 2005 ; Burtscher et al, 2014 ).…”

“…Across the spectrum of these disorders, however, it remains unclear whether the phenotypes arise from decreased protein expression, protein instability, or changes to channel kinetics ( Hoda et al, 2005 ; Burtscher et al, 2014 ). While many studies have sought to establish whether pathogenic variants can be grouped by structural features, residue properties, or topology ( Brunklaus et al, 2014 ; Heyne et al, 2020 ; Indelicato and Boesch, 2021 ; Sadeh et al, 2021 ), it remains the case that a majority of missense mutations, which are identified in a clinical context, lack sufficient evidence to confirm pathogenicity. This frequently results in inappropriate designation ( Hosseini et al, 2018 ) and/or in variants being reported as variants of uncertain significance (VUS), precluding the provision of a molecular diagnosis to patients and families ( Hoda et al, 2005 ).…”