Neuronal ceroid lipofuscinosis: A novel gene (CLN8) is mutated in human progressive epilepsy with mental retardation and the motor neuron degeneration mouse model. S. Ranta1, Y. Zhang2, L. Lonka1, A. Messer3, S. Mole4, R. Wheeler4, J. Sharp4, A. Hirvasniemi5, A. de la Chapelle1, T.C. Gilliam2, A-E. Lehesjoki1. 1) Folkhälsan Institute of Genetics, Helsinki, Finland and Dept. of Medical Genetics, University of Helsinki; 2) Depts. of Psychiatry, Genetics and Development, and Columbia Genome Center, Columbia University, New York, NY; 3) Wadsworth Center, David Axelrod Institute, NY State Dept. of Health, Albany, NY; 4) Dept. of Paediatrics, Royal Free and University College Medical School, University College London, United Kingdom; 5) Dept. of Pediatrics, Kainuu Central Hospital, Finland.
Progressive epilepsy with mental retardation (EPMR), an autosomal recessive disorder characterized by onset of generalized seizures between the age of 5 and 10 years and subsequent progressive mental retardation, was recently recognized as a new subtype (CLN8) of neuronal ceroid lipofuscinosis. NCL comprises a group of progressive encephalopathies characterized by the accumulation of autofluorescent lipopigment in various tissues. A missense mutation (70C>G) cosegregating fully with the disease phenotype in all EPMR patients was identified in a novel putative transmembrane protein with no homology to previously known genes or proteins. It was not found in homozygosity in any of 433 control individuals. We assembled the homologous mouse gene (Cln8) sequence from EST clones. At the nucleotide and polypeptide level the human and mouse genes were 82% and 85% identical, respectively. The human mutation site, arginine 24 was conserved in the mouse gene. We localized the mouse gene to the same region as the motor neuron degeneration mouse (mnd), a naturally occurring model for NCL. In mnd/mnd mice a homozygous 1 bp insertion 267-268insC predicting a frame shift and a truncated protein was identified in the Cln8 gene. These data indicate that defects in these orthologous genes underlie NCL disease phenotypes in human and mouse. The identification of the disease gene underlying the mnd mouse is the first description of the genetic basis of a naturally occuring animal model for NCL.