title: The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8.
abstract: The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation. Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C-->G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki, Finland. susanna.ranta@helsinki.fi
authors.forename: S
authors.initials: S
authors.lastname: Ranta
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Ross
authors.forename: L
authors.initials: L
authors.lastname: Lonka
authors.forename: E
authors.initials: E
authors.lastname: Takkunen
authors.forename: A
authors.initials: A
authors.lastname: Messer
authors.forename: J
authors.initials: J
authors.lastname: Sharp
authors.forename: R
authors.initials: R
authors.lastname: Wheeler
authors.forename: K
authors.initials: K
authors.lastname: Kusumi
authors.forename: S
authors.initials: S
authors.lastname: Mole
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: M B
authors.initials: MB
authors.lastname: Soares
authors.forename: M F
authors.initials: MF
authors.lastname: Bonaldo
authors.forename: A
authors.initials: A
authors.lastname: Hirvasniemi
authors.forename: A
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: T C
authors.initials: TC
authors.lastname: Gilliam
authors.forename: A E
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005091:Exons; D005192:Family Health; D005260:Female; D005796:Genes / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000150:complications / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
chemical_list: C121767:CLN8 protein, human; C498493:Cln8 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger