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Human Molecular Genetics Advance Access originally published online on October 28, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3349-3358
DOI: 10.1093/hmg/ddg366
© 2003 Oxford University Press

Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns-/-) produced by targeted disruption of the gene defective in Morquio A disease

Shunji Tomatsu1,3,*, Koji O. Orii1,4, Carole Vogler2, Jun Nakayama5, Beth Levy2, Jeffrey H. Grubb1, Monica A. Gutierrez1, Soomin Shim1, Seiji Yamaguchi3, Tatsuo Nishioka1, Adriana Maria Montaño6, Akihiko Noguchi7, Tadao Orii4, Naomi Kondo4 and William S. Sly1

1Edward A. Doisy Department of Biochemistry and Molecular Biology and 2Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA, 3Shimane Medical University, Shimane, Japan, 4Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan, 5Department of Pathology, Shinshu University School of Medicine, Matsumoto, Japan, 6Department of Pediatrics, Cardinal Glennon Children's Hospital, Saint Louis University, St Louis, MO, USA and 7Department of Biosystems Science, Graduate University for Advanced Studies, Kanagawa, Japan

Received August 13, 2003; Revised October 10, 2003; Accepted October 21, 2003

Mucopolysaccharidosis IVA is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme required for the stepwise degradation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). To generate a model for studies of the pathophysiology and of potential therapies, we disrupted exon 2 of Galns, the homologous murine gene. Homozygous Galns-/- mice have no detectable GALNS enzyme activity and show increased urinary glycosaminoglycan (GAGs) levels. These mice accumulate GAGs in multiple tissues including liver, kidney, spleen, heart, brain and bone marrow. At 2 months old, lysosomal storage is present primarily within reticuloendothelial cells such as Kupffer cells and cells of the sinusoidal lining of the spleen. Additionally, by 12 months old, vacuolar change is observed in the visceral epithelial cells of glomeruli and cells at the base of heart valves but it is not present in parenchymal cells such as hepatocytes and renal tubular epithelial cells. In the brain, hippocampal and neocortical neurons and meningeal cells had lysosomal storage. KS and C6S were more abundant in the cytoplasm of corneal epithelial cells of Galns-/- mice compared with wild-type mice by immunohistochemistry. Radiographs revealed no change in the skeletal bones of mice up to 12 months old. Thus, targeted disruption of the murine Galns gene has produced a murine model, which shows visceral storage of GAGs but lacks the skeletal features. The complete absence of GALNS in mutant mice makes them useful for studies of pharmacokinetics and tissue targeting of recombinant GALNS designed for enzyme replacement.

* To whom correspondence should be addressed at: E.A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 S. Grand Blvd, St Louis, MO 63104, USA. Tel: +1 3145778131, Fax: +1 3147761183; Email: tomatsus{at}slu.edu


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