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

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 CACN A1H encoding for Ca v 3.2 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 Ca v 3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominantnegative 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 Ca v 3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Ca v 3.2 channel function. These findings add to the notion that loss-of-function of Ca v 3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

Morphological and Molecular Responses of Lateolabrax maculatus Skeletal Muscle Cells to Different Temperatures

“…RyR-mediated Ca 2+ dynamics have been demonstrated as a universal requirement for skeletal myogenesis [ 53 ]. Ryr1 is responsible for releasing Ca 2+ from the SR to the myoplasm and serca1a functions to uptake Ca 2+ from the myoplasm to the SR which maintains calcium homeostasis [ 53 , 54 , 55 , 56 , 57 , 58 ]. After the intracellular Ca 2+ concentration reaches a certain threshold value, subsequently activating camk2b and forming the Ca 2+ /CaM complex, further inhibiting histone deacetylase II (HDACII) and increasing nuclear abundance of myogenin and myocyte enhancer factor 2 (MEF2) [ 59 ], which synergistically regulate myogenesis and induce the development of skeletal muscle [ 60 , 61 ].…”

Dietary Supplementation of Octacosanol Improves Exercise-Induced Fatigue and Its Molecular Mechanism

“…Interestingly, the microarray assay screened out the protein of calcium voltage-gated channel subunit α1 H (Cacna1h), which could mediate the entry of calcium ions into the excitable cells and have been implicated in a variety of calcium-dependent processes, including muscle fiber development, muscle contraction, and hormone secretion or neurotransmitter release. − Recent publications report that the heterozygous mutation of Cacna1h causes congenital muscular atrophy, probably through dysfunctional Ca 2+ regulation . Deficiency of Cacna1h shows the reduced contractile ability of the muscle .…”

The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels

“…The cells were kept at 30 °C for at least two days before recording. Dorsal root ganglion (DRG) neurons were prepared as described by us previously, with the exception that mouse tissue was used in the present study instead of rat [ 31 , 32 ]. In brief, DRG from 6- to 7-week-old C57 male mice were incubated with 4 mg/ml collagenase (Gibco, Cat#17018-029) and 40 μl/ml papain (Worthington, Cat#LS003126) in culture medium (DMEM (Gibco, Cat#11995) supplemented with 10% heat-inactivated fetal bovine serum (Gibco, Cat#26140-079) and 1% penicillin/Streptomycin (Gibco, Cat#15,140–122)) at 37 °C for 30 min, and then, 1 μg/ml DNase (Sigma, Cat#D5025) at 37 °C for another 10 min, followed by washing and mechanical trituration.…”