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

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.

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

“…Furthermore, the C57BL/6J strain is highly inbred resulting in less variability between individuals than in outbred strains such as CD1. In addition, mouse models for other neuronal ceroid lipofuscinoses, including CLN1, CLN6, and CLN8, have been established on the C57BL/6J strain background (Gupta et al, 2001;Lei et al, 2006;Ranta et al, 1999;Wheeler et al, 2002). Having all mouse NCL mutant models on the same strain background will facilitate phenotypic comparisons between the different mutations.…”

A novel role of the Batten disease gene CLN3: Association with BMP synthesis

“…The genes associated with NCL encode a diverse group of both soluble and membrane bound proteins that reside in multiple cellular compartments. Single deficiencies in any of four soluble proteins, palmitoyl-protein thioesterase-1 [1], tripeptidyl peptidase-1 [2], cathepsin D [3] or cathepsin F [4], or of six membrane bound proteins, CLN3 [5], CLN5 [6], CLN6 [7], CLN8 [8], CLC-3 [9;10] or CLC-7 [11], have been associated with the development of NCL in either human or animal models. CLN3 protein is highly hydrophobic and its expression has been detected in multiple human tissues including brain, pancreatic islets, peripheral nerve, spleen and testis [12].…”

Progression of early postnatal retinal pathology in a mouse model of neuronal ceroid lipofuscinosis

“…1,27 Progressive epilepsy with mental retardation (EPMR), also known as Northern epilepsy, was recently identified as one of the NCL family by accumulation of autofluorescent, intracytoplasmic storage material in CNS neurons. 1,2 Electron microscopic observation revealed curvilinear-like profiles and granular storage material comprising mostly subunit c of mitochondrial ATP synthase. 1 The CLN8 gene underlying EPMR was identified by positional cloning, 2 and found to encode a novel protein of 286 amino acids and an estimated molecular weight of 30 kDa.…”

“…1,2 Electron microscopic observation revealed curvilinear-like profiles and granular storage material comprising mostly subunit c of mitochondrial ATP synthase. 1 The CLN8 gene underlying EPMR was identified by positional cloning, 2 and found to encode a novel protein of 286 amino acids and an estimated molecular weight of 30 kDa. Mutations in the CLN8 gene were found to be associated with not only EPMR patients but also the mnd mouse, a model of motor neuron degeneration.…”

“…Mutations in the CLN8 gene were found to be associated with not only EPMR patients but also the mnd mouse, a model of motor neuron degeneration. 2,26 The CLN8 gene product has been localized to the endoplasmic reticulum (ER), 3 with several putative functions proposed, including protein translocation across ER membranes, channel formation, or other activities in the early secretory pathway.…”