title: Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC.
abstract: Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of α-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marcó
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Roca
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Motas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Molas
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Villacampa
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Cristian S
authors.initials: CS
authors.lastname: Melia
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sánchez
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bertolin
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Ruberte
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Haurigot
authors.affiliation: Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona 08036, Spain fatima.bosch@uab.es.
authors.forename: Fatima
authors.identifier: 0000-0002-7705-5515
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006025:Glycosaminoglycans / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008136:Longevity; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009084:Mucopolysaccharidosis III / Q000201:enzymology / Q000473:pathology*; D009928:Organ Specificity; D016019:Survival Analysis
chemical_list: D006025:Glycosaminoglycans; D000123:Acetyltransferases
keywords: Animal model; HGSNAT; Lysosomal storage disease; MPSIIIC; Neurodegeneration