title: Deletion of the Caenorhabditis elegans homologues of the CLN3 gene, involved in human juvenile neuronal ceroid lipofuscinosis, causes a mild progeric phenotype.
abstract: The CLN3 gene is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten-Spielmeyer-Vogt disease, a severe hereditary neurodegenerative lysosomal storage disorder characterized by progressive disease pathology, with loss of vision as the first symptom. Another characteristic of JNCL is the lysosomal accumulation of autofluorescent lipopigments, forming fingerprint storage patterns visible by electron microscopy. The function of the CLN3 protein is still unknown, although the evolutionarily conserved CLN3 protein is being functionally analysed using different experimental models. We have explored the potential of the nematode Caenorhabditis elegans as a model for Batten disease in order to bridge the gap between the unicellular yeast and very complex mouse JNCL models. C. elegans has three genes homologous to CLN3, for each of which deletion mutants were isolated. Cln-3.1 deletion mutants have a decreased lifespan, and cln-3.2 deletion mutants a decreased brood size. However, the neuronal or movement defects and aberrant lipopigment distribution or accumulation observed in JNCL were not found in the worms. To detect possible redundancy, single deletion mutants were crossed to obtain double and triple mutants, which were viable but showed no JNCL-specific defects. The cln-3 triple mutants show a more prominent decrease in lifespan and brood size, the latter most conspicuously at the end of the egg-laying period, suggesting premature ageing. To focus our functional analysis we examined the C. elegans cln-3 expression patterns, using promoter-GFP (green fluorescent protein) gene fusions. Fluorescence patterns suggest cln-3.1 expression in the intestine, cln-3.2 expression in the hypoderm, and cln-3.3 expression in intestinal muscle, male-specific posterior muscle and hypoderm. Further life stage- and tissue-specific analysis of the processes causing the phenotype of the cln-3 triple mutants may provide more information about the function of the cln-3 protein and contribute to a better understanding of the basic processes affected in Batten disease patients.
authors.affiliation: Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: de Voer
authors.forename: P
authors.initials: P
authors.lastname: van der Bent
authors.forename: A J G
authors.initials: AJ
authors.lastname: Rodrigues
authors.forename: G-J B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: D J M
authors.initials: DJ
authors.lastname: Peters
authors.forename: P E M
authors.initials: PE
authors.lastname: Taschner
mesh_terms: D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans; D050260:Carbohydrate Metabolism; D003360:Cosmids; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D015233:Models, Statistical; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases; D009472:Neuronal Ceroid-Lipofuscinoses / Q000175:diagnosis* / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
chemical_list: C105199:CLN3 protein, human; D017931:DNA Primers; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins