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  Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis

Zanni, G., Cali, T., Kalscheuer, V. M., Ottolini, D., Barresi, S., Lebrun, N., et al. (2012). Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 109(36), 14514-14519. doi:10.1073/pnas.1207488109.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-EC8A-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-EC8B-7
Genre: Journal Article

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 Creators:
Zanni, G., Author
Cali, T., Author
Kalscheuer, V. M.1, Author              
Ottolini, D., Author
Barresi, S., Author
Lebrun, N., Author
Montecchi-Palazzi, L., Author
Hu, H.2, Author              
Chelly, J., Author
Bertini, E., Author
Brini, M., Author
Carafoli, E., Author
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              
2Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              

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Free keywords: Aequorin Amino Acid Sequence Base Sequence Blotting, Western Calcium/*metabolism Cerebellar Ataxia/*genetics DNA Primers/genetics Genetic Diseases, X-Linked/*genetics HeLa Cells Homeostasis/*genetics Humans *Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Mutation/genetics Neurons/*metabolism Pedigree Plasma Membrane Calcium-Transporting ATPases/chemistry/*genetics Protein Isoforms/genetics Sequence Analysis, DNA
 Abstract: Ca(2+) in neurons is vital to processes such as neurotransmission, neurotoxicity, synaptic development, and gene expression. Disruption of Ca(2+) homeostasis occurs in brain aging and in neurodegenerative disorders. Membrane transporters, among them the calmodulin (CaM)-activated plasma membrane Ca(2+) ATPases (PMCAs) that extrude Ca(2+) from the cell, play a key role in neuronal Ca(2+) homeostasis. Using X-exome sequencing we have identified a missense mutation (G1107D) in the CaM-binding domain of isoform 3 of the PMCAs in a family with X-linked congenital cerebellar ataxia. PMCA3 is highly expressed in the cerebellum, particularly in the presynaptic terminals of parallel fibers-Purkinje neurons. To study the effects of the mutation on Ca(2+) extrusion by the pump, model cells (HeLa) were cotransfected with expression plasmids encoding its mutant or wild-type (wt) variants and with the Ca(2+)-sensing probe aequorin. The mutation reduced the ability of the PMCA3 pump to control the cellular homeostasis of Ca(2+). It significantly slowed the return to baseline of the Ca(2+) transient induced by an inositol-trisphosphate (InsP(3))-linked plasma membrane agonist. It also compromised the ability of the pump to oppose the influx of Ca(2+) through the plasma membrane capacitative channels.

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Language(s): eng - English
 Dates: 2012-08-212012-09-04
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1207488109
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: National Academy of Sciences
Pages: - Volume / Issue: 109 (36) Sequence Number: - Start / End Page: 14514 - 14519 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230