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Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis
Authors:Nosková Lenka  Stránecký Viktor  Hartmannová Hana  Přistoupilová Anna  Barešová Veronika  Ivánek Robert  Hůlková Helena  Jahnová Helena  van der Zee Julie  Staropoli John F  Sims Katherine B  Tyynelä Jaana  Van Broeckhoven Christine  Nijssen Peter C G  Mole Sara E  Elleder Milan  Kmoch Stanislav
Affiliation:1Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic;2Center for Applied Genomics, First Faculty of Medicine, Charles University in Prague, 120 00 Prague, Czech Republic;3Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, B-2610 Antwerp, Belgium;4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, B-2610 Antwerp, Belgium;5Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;6Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, 00014 Helsinki, Finland;7Department of Neurology, St. Elisabeth Hospital, 5022 Tilburg, The Netherlands;8MRC Laboratory for Molecular Cell Biology, Institute of Child Health and Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK
Abstract:Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.
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