title: A Novel Mutation in Isoform 3 of the Plasma Membrane Ca2+ Pump Impairs Cellular Ca2+ Homeostasis in a Patient with Cerebellar Ataxia and Laminin Subunit 1α Mutations.
abstract: The particular importance of Ca(2+) signaling to neurons demands its precise regulation within their cytoplasm. Isoform 3 of the plasma membrane Ca(2+) ATPase (the PMCA3 pump), which is highly expressed in brain and cerebellum, plays an important role in the regulation of neuronal Ca(2+). A genetic defect of the PMCA3 pump has been described in one family with X-linked congenital cerebellar ataxia. Here we describe a novel mutation in the ATP2B3 gene in a patient with global developmental delay, generalized hypotonia and cerebellar ataxia. The mutation (a R482H replacement) impairs the Ca(2+) ejection function of the pump. It reduces the ability of the pump expressed in model cells to control Ca(2+) transients generated by cell stimulation and impairs its Ca(2+) extrusion function under conditions of low resting cytosolic Ca(2+) as well. In silico analysis of the structural effect of the mutation suggests a reduced stabilization of the portion of the pump surrounding the mutated residue in the Ca(2+)-bound state. The patient also carries two missense mutations in LAMA1, encoding laminin subunit 1α. On the basis of the family pedigree of the patient, the presence of both PMCA3 and laminin subunit 1α mutations appears to be necessary for the development of the disease. Considering the observed defect in cellular Ca(2+) homeostasis and the previous finding that PMCAs act as digenic modulators in Ca(2+)-linked pathologies, the PMCA3 dysfunction along with LAMA1 mutations could act synergistically to cause the neurological phenotype.
authors.affiliation: From the Departments of Biology and.
authors.forename: Tito
authors.initials: T
authors.lastname: Calì
authors.affiliation: Biomedical Sciences University of Padova, 35131 Padova, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lopreiato
authors.affiliation: Mallinckrodt Institute of Radiology and.
authors.forename: Joshua
authors.initials: J
authors.lastname: Shimony
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-1093.
authors.forename: Marisa
authors.initials: M
authors.lastname: Vineyard
authors.affiliation: Biomedical Sciences University of Padova, 35131 Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Frizzarin
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 00165 Rome, Italy, and.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
authors.affiliation: Biomedical Sciences University of Padova, 35131 Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.affiliation: From the Departments of Biology and marisa.brini@unipd.it.
authors.forename: Marisa
authors.initials: M
authors.lastname: Brini
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri 63110-1093, Shinawi_M@kids.wustl.edu.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), 35131 Padova, Italy ernesto.carafoli@unipd.it.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Carafoli
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism*; D002648:Child; D005260:Female; D006706:Homeostasis; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D007797:Laminin; C084098:laminin A; D053499:Plasma Membrane Calcium-Transporting ATPases; C506962:ATP2B3 protein, human; D002118:Calcium
keywords: ataxia; calcium; calcium ATPase; enzyme mutation; laminin