A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2\u2009T-type channel activity

Robin N Stringer,Norbert Weiss,Gerald W Zamponi,Omid Haji-Ghassemi,Sun Huang,Anna Liashenko,Ivana A Souza,Romane Idoux,Filip Van Petegem,Bohumila Jurkovicova-Tarabova,Yuriy Rzhepetskyy,Lubica Lacinova,Roger Pamphlett

doi:10.1186/s13041-020-00577-6

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

Highlights

Amyotrophic lateral sclerosis (ALS), known as motor neuron disease or Lou Gehrig’s disease, is a heterogeneous neuromuscular disease characterized by the degeneration of cortical, brain stem and spinal motor neurons that leads to muscle weakness and paralysis
Whole genome sequencing identifies heterozygous CACN A1H mutations in ALS patients In a previous study, using case-unaffected parents trio exome analyses, we reported an ALS patient with two heterozygous CACNA1H missense mutations causing a partial loss-of-function of Cav3.2 channel, suggesting
While several common genes are implicated in familial ALS, the occurrence of rare genetic variants in patients with no family history of the disease has emerged as a potential contributing factor in sporadic ALS [11]

Summary

Introduction

Amyotrophic lateral sclerosis (ALS), known as motor neuron disease or Lou Gehrig’s disease, is a heterogeneous neuromuscular disease characterized by the degeneration of cortical, brain stem and spinal motor neurons that leads to muscle weakness and paralysis. Several genes and loci in apparent sALS patients have been proposed to be associated with an increased risk of ALS, or to modify the onset or progression of the disease, which highlights the importance of genetic risk factors [6]. Among these genes, the most prominent are ATXN2 [7], UNC13A [8], ANG [9], and SMN1 [10]. Functional analysis of these two variants revealed a complete loss of Cav3.2 channel function associated with the ΔI153 variant and a dominant-negative effect of this variant on the wild-type channel when expressed in trans

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