The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8

Nat Genet. 1999 Oct;23(2):233-6. doi: 10.1038/13868.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Blotting, Northern
  • Chromosome Mapping
  • DNA Mutational Analysis
  • Epilepsy / complications
  • Epilepsy / genetics*
  • Exons
  • Family Health
  • Female
  • Genes / genetics
  • Humans
  • Intellectual Disability / complications
  • Intellectual Disability / genetics*
  • Introns
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutagenesis, Insertional
  • Mutation
  • Neuronal Ceroid-Lipofuscinoses / complications
  • Neuronal Ceroid-Lipofuscinoses / genetics*
  • Pedigree
  • Point Mutation
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Tissue Distribution


  • CLN8 protein, human
  • Cln8 protein, mouse
  • Membrane Proteins
  • RNA, Messenger

Associated data

  • GENBANK/AA368223
  • GENBANK/AA515629
  • GENBANK/AA563326
  • GENBANK/AA765593
  • GENBANK/AA771241
  • GENBANK/AA807426
  • GENBANK/AA921233
  • GENBANK/AF123757
  • GENBANK/AF123758
  • GENBANK/AF123759
  • GENBANK/AF123760
  • GENBANK/AF123761
  • GENBANK/AF125307
  • GENBANK/AF125308
  • GENBANK/AI246377