A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations

Mattia Vicario, Tito Calì, Domenico Cieri, Francesca Vallese, Raissa Bortolotto, Raffaele Lopreiato, Francesco Zonta, Marta Nardella, Alessia Micalizzi, Dirk J. Lefeber, Enza Maria Valente, Enrico Bertini, Giuseppe Zanotti, Ginevra Zanni, Marisa Brini, Ernesto Carafoli

Research output: Contribution to journalArticlepeer-review


The neuron-restricted isoform 3 of the plasma membrane Ca2 + ATPase plays a major role in the regulation of Ca2 + homeostasis in the brain, where the precise control of Ca2 + signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca2 + handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca2 +-linked pathologies.
Original languageEnglish
Pages (from-to)3303-3312
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number12
Publication statusPublished - Dec 1 2017


  • Calcium signaling
  • Phosphomannomutase 2 mutation
  • Plasma membrane calcium ATPases
  • Pump mutation
  • X-linked cerebellar ataxia


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