title: Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease.
abstract: Mutations in the major facilitator superfamily domain containing 8 (MFSD8) gene coding for the lysosomal CLN7 membrane protein result in CLN7 disease, a lysosomal storage disease of childhood. CLN7 disease belongs to a group of inherited disorders, called neuronal ceroid lipofuscinoses (NCL), which are characterized by the accumulation of autofluorescent ceroid lipopigments, neuroinflammation, photoreceptor- and neurodegeneration. We have disrupted the Mfsd8 gene by insertion of a lacZ gene-trap cassette between exons 1 and 2 in mice and have analyzed the impact of Cln7 depletion on neuronal and visceral tissues. Analysis of lacZ reporter gene activity in heterozygous Mfsd8((wt/tm1a)) mice showed strong Mfsd8 mRNA expression in the cerebral cortex, in the hippocampus and in the kidney. Homozygous Mfsd8((tm1a/tm1a)) mice were viable and fertile and resembled biochemically the NCL-phenotype of human CLN7 patients including the accumulation of autofluorescent material in the brain and peripheral tissues and of subunit c of mitochondrial ATP synthase in the cerebellum and nuclei of distinct brain regions, and the degeneration of photoreceptor cells in the retina. Lysosomal storage was found in large neurons of the medulla, the hippocampus and in Purkinje cells of the cerebellum in mutant mice. The ultrastructure of the storage material revealed dense lamellar bodies with irregular forms within cerebellar and hippocampal neurons. In the brain loss of Cln7 was accompanied by mild reactive microgliosis and subtle astrogliosis by 10months of age, respectively. In summary we have generated a mouse model which is partly valuable as some but not all neuropathological features of human CLN7 disease are recapitulated thus representing an animal model to study CLN7-specific disease mechanisms.
authors.affiliation: Biochemistry I, Department of Chemistry, Bielefeld University, 33615 Bielefeld, Germany. Electronic address: mdamme@biochem.uni-kiel.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Damme
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: l.brandenstein@uke.de.
authors.forename: Laura
authors.initials: L
authors.lastname: Brandenstein
authors.affiliation: Center for Molecular Neurobiology Hamburg, ZMNH, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: susanne.fehr@zmnh.uni-hamburg.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fehr
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: wandajankowiak@hotmail.com.
authors.forename: Wanda
authors.initials: W
authors.lastname: Jankowiak
authors.affiliation: Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: u.bartsch@uke.de.
authors.forename: Udo
authors.initials: U
authors.lastname: Bartsch
authors.affiliation: Center for Molecular Neurobiology Hamburg, ZMNH, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: michaela.schweizer@zmnh.uni-hamburg.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Center for Molecular Neurobiology Hamburg, ZMNH, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: hermans@zmnh.uni-hamburg.de.
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: storch@uke.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Storch
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D008099:Liver / Q000201:enzymology; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D043323:alpha-Mannosidase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: C522398:MFSD8 protein, human; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D001616:beta-Galactosidase; D043323:alpha-Mannosidase; D001619:beta-N-Acetylhexosaminidases
keywords: CLN7 disease; CLN7/MFSD8; Cln7 mouse; Lysosomal membrane protein; Lysosomal storage disease; Lysosomes; Major facilitator superfamily; NCL; Neuronal ceroid lipofuscinosis