A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia

Mattia Vicario, Ginevra Zanni, Francesca Vallese, Filippo Santorelli, Alessandro Grinzato, Domenico Cieri, Paola Berto, Martina Frizzarin, Raffaele Lopreiato, Francesco Zonta, Stefania Ferro, Michele Sandre, Oriano Marin, Maria Ruzzene, Enrico Bertini, Giuseppe Zanotti, Marisa Brini, Tito Calì, Ernesto Carafoli

Research output: Contribution to journalArticle

Abstract

The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca2+ signaling in neurons demands the continuous activity of Ca2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca2+ATPases (PMCA pumps) play a key role in the regulation of Ca2+ handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca2+ ejection.

Original languageEnglish
Pages (from-to)157-166
Number of pages10
JournalNeurobiology of Disease
Volume115
DOIs
Publication statusPublished - Jul 2018

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Ataxia
Calmodulin
Cerebellar Ataxia
Protein Isoforms
Cadherins
Mutation
Cell Membrane
Membrane Microdomains
Genes
Neurons
Calcium-Transporting ATPases
Medical Genetics
Eukaryotic Cells
Deafness
Missense Mutation
Molecular Dynamics Simulation
Hearing Loss
Nervous System
Neurotransmitter Agents
Cations

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A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia. / Vicario, Mattia; Zanni, Ginevra; Vallese, Francesca; Santorelli, Filippo; Grinzato, Alessandro; Cieri, Domenico; Berto, Paola; Frizzarin, Martina; Lopreiato, Raffaele; Zonta, Francesco; Ferro, Stefania; Sandre, Michele; Marin, Oriano; Ruzzene, Maria; Bertini, Enrico; Zanotti, Giuseppe; Brini, Marisa; Calì, Tito; Carafoli, Ernesto.

In: Neurobiology of Disease, Vol. 115, 07.2018, p. 157-166.

Research output: Contribution to journalArticle

Vicario, M, Zanni, G, Vallese, F, Santorelli, F, Grinzato, A, Cieri, D, Berto, P, Frizzarin, M, Lopreiato, R, Zonta, F, Ferro, S, Sandre, M, Marin, O, Ruzzene, M, Bertini, E, Zanotti, G, Brini, M, Calì, T & Carafoli, E 2018, 'A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia', Neurobiology of Disease, vol. 115, pp. 157-166. https://doi.org/10.1016/j.nbd.2018.04.009
Vicario, Mattia ; Zanni, Ginevra ; Vallese, Francesca ; Santorelli, Filippo ; Grinzato, Alessandro ; Cieri, Domenico ; Berto, Paola ; Frizzarin, Martina ; Lopreiato, Raffaele ; Zonta, Francesco ; Ferro, Stefania ; Sandre, Michele ; Marin, Oriano ; Ruzzene, Maria ; Bertini, Enrico ; Zanotti, Giuseppe ; Brini, Marisa ; Calì, Tito ; Carafoli, Ernesto. / A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia. In: Neurobiology of Disease. 2018 ; Vol. 115. pp. 157-166.
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abstract = "The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca2+ signaling in neurons demands the continuous activity of Ca2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca2+ATPases (PMCA pumps) play a key role in the regulation of Ca2+ handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca2+ ejection.",
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T1 - A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia

AU - Vicario, Mattia

AU - Zanni, Ginevra

AU - Vallese, Francesca

AU - Santorelli, Filippo

AU - Grinzato, Alessandro

AU - Cieri, Domenico

AU - Berto, Paola

AU - Frizzarin, Martina

AU - Lopreiato, Raffaele

AU - Zonta, Francesco

AU - Ferro, Stefania

AU - Sandre, Michele

AU - Marin, Oriano

AU - Ruzzene, Maria

AU - Bertini, Enrico

AU - Zanotti, Giuseppe

AU - Brini, Marisa

AU - Calì, Tito

AU - Carafoli, Ernesto

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/7

Y1 - 2018/7

N2 - The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca2+ signaling in neurons demands the continuous activity of Ca2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca2+ATPases (PMCA pumps) play a key role in the regulation of Ca2+ handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca2+ ejection.

AB - The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca2+ oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca2+ homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca2+ signaling in neurons demands the continuous activity of Ca2+ pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane Ca2+ATPases (PMCA pumps) play a key role in the regulation of Ca2+ handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca2+ ejection.

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