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

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 pathophys...

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Veröffentlicht in:Human molecular genetics 2003-12, Vol.12 (24), p.3349-3358
Hauptverfasser: Tomatsu, Shunji, Orii, Koji O., Vogler, Carole, Nakayama, Jun, Levy, Beth, Grubb, Jeffrey H., Gutierrez, Monica A., Shim, Soomin, Yamaguchi, Seiji, Nishioka, Tatsuo, Montaño, Adriana Maria, Noguchi, Akihiko, Orii, Tadao, Kondo, Naomi, Sly, William S.
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container_end_page 3358
container_issue 24
container_start_page 3349
container_title Human molecular genetics
container_volume 12
creator Tomatsu, Shunji
Orii, Koji O.
Vogler, Carole
Nakayama, Jun
Levy, Beth
Grubb, Jeffrey H.
Gutierrez, Monica A.
Shim, Soomin
Yamaguchi, Seiji
Nishioka, Tatsuo
Montaño, Adriana Maria
Noguchi, Akihiko
Orii, Tadao
Kondo, Naomi
Sly, William S.
description 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.
doi_str_mv 10.1093/hmg/ddg366
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Mol. Genet</addtitle><description>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. 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Biological and molecular evolution</subject><subject>glycosaminoglycans</subject><subject>Human</subject><subject>keratan sulfate</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mucopolysaccharidosis IV - genetics</subject><subject>Mucopolysaccharidosis IV - pathology</subject><subject>N-acetylgalactosamine-6-sulfate sulfatase</subject><subject>Phenotype</subject><subject>Recombination, Genetic</subject><subject>Stem Cells</subject><issn>0964-6906</issn><issn>1460-2083</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9qFDEcB_BBFLtWLz6ABEFRYdxk8m9yLIu2SlsvRYuXkMn8Zps6M9kmGXHfwLN3X84nMessFrx4CAnkk98vybcoHhP8mmBFl1fDetm2ayrEnWJBmMBlhWt6t1hgJVgpFBYHxYMYrzEmglF5vzggjNeUMbEofp75KQIafAs98h06L42FtO3Xpjc2-WgGN0Ipyjj1nUmA5tnkIy10zjoY7Ra9ODb9GH99_7HM4yXaBN9OFlrUbFEyYQ0pr1sXw7RJzo-7NukK0BrGP1XAJvcVkBvRmQ83k_PoaKchN3lY3OtMH-HRfj4sLt6-uVidlKcfjt-tjk5LyxhPZceMUrJtOiMYl7USTQO04QK3RAhlgQlT8YrVFWm6uqmlMZJjZoGbTkng9LB4PpfNN7-ZICY9uGih780I-Xu0JKzCnP0fElURiYXK8Ok_8NpPYcxv0BUhFadKsoxezcgGH2OATm-CG0zYaoL1Llmdk9Vzshk_2VecmgHaW7qPMoNne2CiNX0XzGhdvHWcVpLVO1fOzsUE3_7um_BFC0kl1yeXn7U6X9GPny7fa0x_A25lvvg</recordid><startdate>20031215</startdate><enddate>20031215</enddate><creator>Tomatsu, Shunji</creator><creator>Orii, Koji O.</creator><creator>Vogler, Carole</creator><creator>Nakayama, Jun</creator><creator>Levy, Beth</creator><creator>Grubb, Jeffrey H.</creator><creator>Gutierrez, Monica A.</creator><creator>Shim, Soomin</creator><creator>Yamaguchi, Seiji</creator><creator>Nishioka, Tatsuo</creator><creator>Montaño, Adriana Maria</creator><creator>Noguchi, Akihiko</creator><creator>Orii, Tadao</creator><creator>Kondo, Naomi</creator><creator>Sly, William S.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20031215</creationdate><title>Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease</title><author>Tomatsu, Shunji ; Orii, Koji O. ; Vogler, Carole ; Nakayama, Jun ; Levy, Beth ; Grubb, Jeffrey H. ; Gutierrez, Monica A. ; Shim, Soomin ; Yamaguchi, Seiji ; Nishioka, Tatsuo ; Montaño, Adriana Maria ; Noguchi, Akihiko ; Orii, Tadao ; Kondo, Naomi ; Sly, William S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-f4a997dbfa6457896bbe3b560d1669ce46a2524821bf8b87aa7504ce5af97e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Chimera</topic><topic>chondroitin-6-sulfate</topic><topic>Chondroitinsulfatases - deficiency</topic><topic>Chondroitinsulfatases - genetics</topic><topic>Classical genetics, quantitative genetics, hybrids</topic><topic>Disease Models, Animal</topic><topic>Fundamental and applied biological sciences. 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Biological and molecular evolution</topic><topic>glycosaminoglycans</topic><topic>Human</topic><topic>keratan sulfate</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mucopolysaccharidosis IV - genetics</topic><topic>Mucopolysaccharidosis IV - pathology</topic><topic>N-acetylgalactosamine-6-sulfate sulfatase</topic><topic>Phenotype</topic><topic>Recombination, Genetic</topic><topic>Stem Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tomatsu, Shunji</creatorcontrib><creatorcontrib>Orii, Koji O.</creatorcontrib><creatorcontrib>Vogler, Carole</creatorcontrib><creatorcontrib>Nakayama, Jun</creatorcontrib><creatorcontrib>Levy, Beth</creatorcontrib><creatorcontrib>Grubb, Jeffrey H.</creatorcontrib><creatorcontrib>Gutierrez, Monica A.</creatorcontrib><creatorcontrib>Shim, Soomin</creatorcontrib><creatorcontrib>Yamaguchi, Seiji</creatorcontrib><creatorcontrib>Nishioka, Tatsuo</creatorcontrib><creatorcontrib>Montaño, Adriana Maria</creatorcontrib><creatorcontrib>Noguchi, Akihiko</creatorcontrib><creatorcontrib>Orii, Tadao</creatorcontrib><creatorcontrib>Kondo, Naomi</creatorcontrib><creatorcontrib>Sly, William S.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tomatsu, Shunji</au><au>Orii, Koji O.</au><au>Vogler, Carole</au><au>Nakayama, Jun</au><au>Levy, Beth</au><au>Grubb, Jeffrey H.</au><au>Gutierrez, Monica A.</au><au>Shim, Soomin</au><au>Yamaguchi, Seiji</au><au>Nishioka, Tatsuo</au><au>Montaño, Adriana Maria</au><au>Noguchi, Akihiko</au><au>Orii, Tadao</au><au>Kondo, Naomi</au><au>Sly, William S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum. Mol. Genet</addtitle><date>2003-12-15</date><risdate>2003</risdate><volume>12</volume><issue>24</issue><spage>3349</spage><epage>3358</epage><pages>3349-3358</pages><issn>0964-6906</issn><issn>1460-2083</issn><eissn>1460-2083</eissn><coden>HNGEE5</coden><abstract>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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>14583446</pmid><doi>10.1093/hmg/ddg366</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals
subjects Animals
Biological and medical sciences
Chimera
chondroitin-6-sulfate
Chondroitinsulfatases - deficiency
Chondroitinsulfatases - genetics
Classical genetics, quantitative genetics, hybrids
Disease Models, Animal
Fundamental and applied biological sciences. Psychology
Galns gene
Gene Targeting
Genetics of eukaryotes. Biological and molecular evolution
glycosaminoglycans
Human
keratan sulfate
Mice
Mice, Knockout
Mucopolysaccharidosis IV - genetics
Mucopolysaccharidosis IV - pathology
N-acetylgalactosamine-6-sulfate sulfatase
Phenotype
Recombination, Genetic
Stem Cells
title Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease
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