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 Cav3.2 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 Cav3.2 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.

b Nuffield Department of Clinical Neurosciences John Radcliffe Hospital University of Oxford Oxford UK

c The Stacey MND Laboratory Discipline of Pathology The University of Sydney Sydney NSW Australia

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague Czech Republic

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The T-type calcium channelosome

Pathophysiology of ion channels in amyotrophic lateral sclerosis

Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss

Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia

De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

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

Genetic T-type calcium channelopathies

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy

The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Cav3.2 channels