Abstract
The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues1. Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype2 (CLN8). It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation3. 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.
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Acknowledgements
We thank the EPMR families for their cooperation; T. Alitalo and J. Kere for providing Finnish control DNA samples; M. Fox for FISH analysis of BAC clones; A. Kerrebrock and E. Lander for the background work on the genetic/physical map of the mnd critical region; and M. Gardiner for the critical reading of our manuscript. This study was supported by The Academy of Finland, The Sigrid Juselius Foundation, The Ulla Hjelt Foundation, The Finnish State Grant TYH8310, the Children's Brain Disease Foundation, NIH Grant NS29110 and the Wellcome Trust, UK (054606/Z/98/Z).
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Ranta, S., Zhang, Y., Ross, B. et al. The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Nat Genet 23, 233–236 (1999). https://doi.org/10.1038/13868
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DOI: https://doi.org/10.1038/13868
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