CACNA1Hmissense mutations associated with amyotrophic lateral sclerosis alter Ca_v3.2 T-type calcium channel activity and reticular thalamic neuron firing

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. In a recent study by Steinberg and colleagues, 2 recessive missense mutations were identified in the Ca v 3.2 T-type calcium channel gene (CACNA1H), in a family with an affected proband (early onset, long duration ALS) and 2 unaffected parents. We have introduced and functionally characterized these mutations using transiently expressed human Ca v 3.2 channels in tsA-201 cells. Both of these mutations produced mild but significant changes on T-type channel activity that are consistent with a loss of channel function. Computer modeling in thalamic reticular neurons suggested that these mutations result in decreased neuronal excitability of thalamic structures. Taken together, these findings implicate CACNA1H as a susceptibility gene in amyotrophic lateral sclerosis.

Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants

“…Genetic variation in the Ral Guanine Nucleotide Dissociation Stimulator Like 1 (RGL1) gene, has been associated with attention (73) and conduct problems among children with attention deficit hyperactivity disorder (74). Additionally, genetic mutations within CACNA1H, which encodes for a subunit of a voltage gated calcium channel, lead to decreased calcium channel activity in neuronal cells, and have been linked to ASD (75), to epilepsy (76), and to amyotrophic lateral sclerosis (77). Overall, these findings suggest that our NNNS-associated epigenetic variations occurred at numerous genomic regions with recognized roles in neurodevelopmental or neurodegenerative disorders, which may provide a link between preterm birth and poorer neurodevelopmental outcomes.…”

Genetic T-type calcium channelopathies

“…117 Functional analysis revealed that these mutations cause a mild alteration of Ca v 3.2 activity that is consistent with a loss-of-function of the channel (table 1). 118 In addition, computer simulations suggested decreased neuronal activity of nerve cells expressing the channel variants.…”

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy

“…Recently, whole exome sequence analysis has identified two compound heterozygous recessive missense mutations in the gene CACNA1H in a patient with ALS [4,5]. CACNA1H encodes for Ca v 3.2 channel, a member of the voltage-gated calcium channel family [6].…”

“…Through their ability to support low-threshold calcium influx (T-type current), they serve essential physiological processes including neuronal firing, hormone secretion, smooth muscle contraction, and myoblast fusion [8]. Their physiological implication is further exemplified by the existence of polymorphisms in CACNA1H associated with a number of human disorders including several forms of epilepsy [9], autism spectrum disorders [10,11], congenital pain [12], primary aldosteronism [13,14], and ALS [4,5].…”