title: A novel mouse model of a patient mucolipidosis II mutation recapitulates disease pathology.
abstract: Mucolipidosis II (MLII) is a lysosomal storage disorder caused by loss of N-acetylglucosamine-1-phosphotransferase, which tags lysosomal enzymes with a mannose 6-phosphate marker for transport to the lysosome. In MLII, the loss of this marker leads to deficiency of multiple enzymes and non-enzymatic proteins in the lysosome, leading to the storage of multiple substrates. Here we present a novel mouse model of MLII homozygous for a patient mutation in the GNPTAB gene. Whereas the current gene knock-out mouse model of MLII lacks some of the characteristic features of the human disease, our novel mouse model more fully recapitulates the human pathology, showing growth retardation, skeletal and facial abnormalities, increased circulating lysosomal enzymatic activities, intracellular lysosomal storage, and reduced life span. Importantly, MLII behavioral deficits are characterized for the first time, including impaired motor function and psychomotor retardation. Histological analysis of the brain revealed progressive neurodegeneration in the cerebellum with severe Purkinje cell loss as the underlying cause of the ataxic gait. In addition, based on the loss of Npc2 (Niemann-Pick type C 2) protein expression in the brain, the mice were treated with 2-hydroxypropyl-β-cyclodextrin, a drug previously reported to rescue Purkinje cell death in a mouse model of Niemann-Pick type C disease. No improvement in brain pathology was observed. This indicates that cerebellar degeneration is not primarily triggered by loss of Npc2 function. This study emphasizes the value of modeling MLII patient mutations to generate clinically relevant mouse mutants to elucidate the pathogenic molecular pathways of MLII and address their amenability to therapy.
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Leigh
authors.initials: L
authors.lastname: Paton
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bitoun
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Janet
authors.initials: J
authors.lastname: Kenyon
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Priestman
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Edwards
authors.affiliation: Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy, and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, United Kingdom and. Electronic address: kay.davies@dpag.ox.ac.uk.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005079:Excipients / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009081:Mucolipidoses / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009154:Mutation; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011689:Purkinje Cells / Q000201:enzymology / Q000473:pathology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D005079:Excipients; D006023:Glycoproteins; C104585:NPC2 protein, human; C497045:Npc2 protein, mouse; D033921:Vesicular Transport Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; C548056:GNPTAB protein, mouse
keywords: Ataxia; Drug Action; Lysosomal Storage Disease; Mouse Genetics; Mucolipidosis II; NPC2; Neurodegeneration
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