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 |
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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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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.</description><identifier>ISSN: 0964-6906</identifier><identifier>ISSN: 1460-2083</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddg366</identifier><identifier>PMID: 14583446</identifier><identifier>CODEN: HNGEE5</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>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</subject><ispartof>Human molecular genetics, 2003-12, Vol.12 (24), p.3349-3358</ispartof><rights>2004 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Dec 15, 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-f4a997dbfa6457896bbe3b560d1669ce46a2524821bf8b87aa7504ce5af97e53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15327486$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14583446$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><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><title>Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns−/−) produced by targeted disruption of the gene defective in Morquio A disease</title><title>Human molecular genetics</title><addtitle>Hum. 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. 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.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Chimera</subject><subject>chondroitin-6-sulfate</subject><subject>Chondroitinsulfatases - deficiency</subject><subject>Chondroitinsulfatases - genetics</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>Disease Models, Animal</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Galns gene</subject><subject>Gene Targeting</subject><subject>Genetics of eukaryotes. 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. Psychology</topic><topic>Galns gene</topic><topic>Gene Targeting</topic><topic>Genetics of eukaryotes. 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 & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & 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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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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