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

Susanna Ranta, Yonghui Zhang, Barbara Ross, Liina Lonka, Elina Takkunen, Anne Messer, Julie Sharp, Ruth Wheeler, Kenro Kusumi, Sara Mole, Wencheng Liu, Marcelo Bento Soares, Maria De Fatima Bonaldo, Aune Hirvasniemi, Albert De La Chapelle, T. Conrad Gilliam, Anna Elina Lehesjoki

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)233-236
Number of pages4
JournalNature Genetics
Volume23
Issue number2
DOIs
StatePublished - Oct 1999
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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