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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


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
Publication statusPublished - Jul 2018
Externally publishedYes


  • Calcium signaling
  • Cerebellar ataxia
  • Plasma membrane calcium ATPases
  • Pump mutation


Dive into the research topics of 'A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia'. Together they form a unique fingerprint.

Cite this