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- Title
The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8.
- Authors
Ranta, Susanna; Zhang, Yonghui; Ross, Barbara; Lonka, Liina; Takkunen, Elina; Messer, Anne; Sharp, Julie; Wheeler, Ruth; Kusumi, Kenro; Mole, Sara; Liu, Wencheng; Soares, Marcelo Bento; de Fatima Bonaldo, Maria; Hirvasniemi, Aune; Chapelle, Albert de la; Gilliam, T. Conrad; Lehesjoki, Anna-Elina
- 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 CIn8 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.
- Subjects
NEURONAL ceroid-lipofuscinosis; INBORN errors of metabolism; INTELLECTUAL disabilities; GENETIC mutation
- Publication
Nature Genetics, 1999, Vol 23, Issue 2, p233
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/13868