title: Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.
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.
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Nosková
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.forename: Anna
authors.initials: A
authors.lastname: Přistoupilová
authors.forename: Veronika
authors.initials: V
authors.lastname: Barešová
authors.forename: Robert
authors.initials: R
authors.lastname: Ivánek
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.forename: Helena
authors.initials: H
authors.lastname: Jahnová
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: John F
authors.initials: JF
authors.lastname: Staropoli
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
authors.forename: Jaana
authors.initials: J
authors.lastname: Tyynelä
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Peter C G
authors.initials: PC
authors.lastname: Nijssen
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D000328:Adult; D017668:Age of Onset; D001483:Base Sequence; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020090:Chromosome Segregation / Q000235:genetics; D005091:Exons / Q000235:genetics; D005190:Family; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005786:Gene Expression Regulation; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D054878:Lipoylation; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010375:Pedigree; D021381:Protein Transport; D017422:Sequence Analysis, DNA
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein