title: CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3.2 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 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.
authors.affiliation: a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Rzhepetskyy
authors.affiliation: a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lazniewska
authors.affiliation: b Nuffield Department of Clinical Neurosciences , John Radcliffe Hospital, University of Oxford , Oxford , UK.
authors.forename: Iulia
authors.initials: I
authors.lastname: Blesneac
authors.affiliation: c The Stacey MND Laboratory, Discipline of Pathology, The University of Sydney , Sydney , NSW , Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Pamphlett
authors.affiliation: a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D020125:Mutation, Missense; D009474:Neurons / Q000502:physiology*; D013788:Thalamus / Q000166:cytology* / Q000502:physiology; D014162:Transfection
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type
keywords: ALS; CACNA1H; Cav3.2 channel; T-type channel; amyotrophic lateral sclerosis; biophysics; calcium channel; missense mutation