title: Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.
abstract: We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.
authors.affiliation: CHUM Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Cadieux-Dion
authors.forename: E
authors.initials: E
authors.lastname: Andermann
authors.forename: P
authors.initials: P
authors.lastname: Lachance-Touchette
authors.forename: O
authors.initials: O
authors.lastname: Ansorge
authors.forename: C
authors.initials: C
authors.lastname: Meloche
authors.forename: A
authors.initials: A
authors.lastname: Barnabé
authors.forename: R I
authors.initials: RI
authors.lastname: Kuzniecky
authors.forename: F
authors.initials: F
authors.lastname: Andermann
authors.forename: E
authors.initials: E
authors.lastname: Faught
authors.forename: S
authors.initials: S
authors.lastname: Leonberg
authors.forename: J A
authors.initials: JA
authors.lastname: Damiano
authors.forename: S F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: G A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: P
authors.initials: P
authors.lastname: Cossette
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D011110:Polymorphism, Genetic; D017384:Sequence Deletion
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; C088460:cysteine string protein