Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease
Tay-Sachs disease, the prototype of the GM2gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accum...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1994-10, Vol.91 (21), p.9975-9979 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Yamanaka, Shoji Johnson, Mark D. Grinberg, Alex Westphal, Heiner Crawley, Jacqueline N. Tanike, Masako Suzuki, Kinuko Proia, Richard L. |
| description | Tay-Sachs disease, the prototype of the GM2gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system. Rapid mental and motor deterioration starting in the first year of life leads to death by 2-4 years of age. Through the targeted disruption of the mouse Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice displayed |
| doi_str_mv | 10.1073/pnas.91.21.9975 |
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The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system. Rapid mental and motor deterioration starting in the first year of life leads to death by 2-4 years of age. Through the targeted disruption of the mouse Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice displayed <1% of normal β-hexosaminidase A activity and accumulated GM2ganglioside in their central nervous system in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At 3-5 months of age, the mutant mice showed no apparent defects in motor or memory function. These β-hexosaminidase A-deficient mice should be useful for devising strategies to introduce functional enzyme and genes into the central nervous system. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.91.21.9975</identifier><identifier>PMID: 7937929</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Animals ; beta-N-Acetylhexosaminidases - deficiency ; beta-N-Acetylhexosaminidases - genetics ; Cell lines ; Central nervous system ; Child, Preschool ; Disease models ; Exploratory Behavior ; Gangliosides ; Genes ; Genetic Vectors ; Hexosaminidase A ; Humans ; Liver - enzymology ; Lysosomes - enzymology ; Medical research ; Mice ; Mice, Mutant Strains ; Microscopy, Electron ; Motor Activity ; Neurological disorders ; Neurons ; Neurons - pathology ; Neurons - ultrastructure ; Parietal Lobe - pathology ; Pathology ; Recombination, Genetic ; Restriction Mapping ; RNA ; Rodents ; Tay Sachs disease ; Tay-Sachs Disease - enzymology ; Tay-Sachs Disease - genetics</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1994-10, Vol.91 (21), p.9975-9979</ispartof><rights>Copyright 1994 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Oct 11, 1994</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4045-b28745ede0568d982f722e1f8f19a2bcfaf731027b588cf999bb1c3accf824203</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/91/21.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2365745$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2365745$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7937929$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamanaka, Shoji</creatorcontrib><creatorcontrib>Johnson, Mark D.</creatorcontrib><creatorcontrib>Grinberg, Alex</creatorcontrib><creatorcontrib>Westphal, Heiner</creatorcontrib><creatorcontrib>Crawley, Jacqueline N.</creatorcontrib><creatorcontrib>Tanike, Masako</creatorcontrib><creatorcontrib>Suzuki, Kinuko</creatorcontrib><creatorcontrib>Proia, Richard L.</creatorcontrib><title>Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Tay-Sachs disease, the prototype of the GM2gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system. Rapid mental and motor deterioration starting in the first year of life leads to death by 2-4 years of age. Through the targeted disruption of the mouse Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice displayed <1% of normal β-hexosaminidase A activity and accumulated GM2ganglioside in their central nervous system in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At 3-5 months of age, the mutant mice showed no apparent defects in motor or memory function. These β-hexosaminidase A-deficient mice should be useful for devising strategies to introduce functional enzyme and genes into the central nervous system. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.</description><subject>Animals</subject><subject>beta-N-Acetylhexosaminidases - deficiency</subject><subject>beta-N-Acetylhexosaminidases - genetics</subject><subject>Cell lines</subject><subject>Central nervous system</subject><subject>Child, Preschool</subject><subject>Disease models</subject><subject>Exploratory Behavior</subject><subject>Gangliosides</subject><subject>Genes</subject><subject>Genetic Vectors</subject><subject>Hexosaminidase A</subject><subject>Humans</subject><subject>Liver - enzymology</subject><subject>Lysosomes - enzymology</subject><subject>Medical research</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Microscopy, Electron</subject><subject>Motor Activity</subject><subject>Neurological disorders</subject><subject>Neurons</subject><subject>Neurons - pathology</subject><subject>Neurons - ultrastructure</subject><subject>Parietal Lobe - pathology</subject><subject>Pathology</subject><subject>Recombination, Genetic</subject><subject>Restriction Mapping</subject><subject>RNA</subject><subject>Rodents</subject><subject>Tay Sachs disease</subject><subject>Tay-Sachs Disease - enzymology</subject><subject>Tay-Sachs Disease - genetics</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1v1DAQxS0EKkvhzAWQxQFO2dqOE8cSFyi0RSoCwXK2HGe88SprL7YD7X9Pol2WjwOnObzfezOjh9BjSpaUiPJs53VaSrpkdCmlqO6gBSWSFjWX5C5aEMJE0XDG76MHKW0IIbJqyAk6EbIUkskFiisd15Chw29diuMuu-BxsDj3gK_gRuNL8IA_QxqHnLDz-IMzgH-43OM3Lpgets7oAWvf4U8692EIa2fwBeg8Rkhz0krfFl-06dO8AXSCh-ie1UOCR4d5ir5evFudXxXXHy_fn7--LgwnvCpa1gheQQekqptONswKxoDaxlKpWWustqKk04Nt1TTGSinblppSG2MbxhkpT9Grfe5ubLfQGfA56kHtotvqeKuCdupvxbtercN3xbnks_3FwR7DtxFSVluXDAyD9hDGpEQtainqagKf_wNuwhj99JpihJaklJJO0NkeMjGkFMEe76BEzU2quUklqWJUzU1Ojqd_nn_kD9VN-suDPht_qb8DlB2HIcNNnshn_yUn4Mke2KQc4pFgZV1NFZQ_AUh9vKo</recordid><startdate>19941011</startdate><enddate>19941011</enddate><creator>Yamanaka, Shoji</creator><creator>Johnson, Mark D.</creator><creator>Grinberg, Alex</creator><creator>Westphal, Heiner</creator><creator>Crawley, Jacqueline N.</creator><creator>Tanike, Masako</creator><creator>Suzuki, Kinuko</creator><creator>Proia, Richard L.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19941011</creationdate><title>Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease</title><author>Yamanaka, Shoji ; Johnson, Mark D. ; Grinberg, Alex ; Westphal, Heiner ; Crawley, Jacqueline N. ; Tanike, Masako ; Suzuki, Kinuko ; Proia, Richard L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4045-b28745ede0568d982f722e1f8f19a2bcfaf731027b588cf999bb1c3accf824203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Animals</topic><topic>beta-N-Acetylhexosaminidases - deficiency</topic><topic>beta-N-Acetylhexosaminidases - genetics</topic><topic>Cell lines</topic><topic>Central nervous system</topic><topic>Child, Preschool</topic><topic>Disease models</topic><topic>Exploratory Behavior</topic><topic>Gangliosides</topic><topic>Genes</topic><topic>Genetic Vectors</topic><topic>Hexosaminidase A</topic><topic>Humans</topic><topic>Liver - enzymology</topic><topic>Lysosomes - enzymology</topic><topic>Medical research</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Microscopy, Electron</topic><topic>Motor Activity</topic><topic>Neurological disorders</topic><topic>Neurons</topic><topic>Neurons - pathology</topic><topic>Neurons - ultrastructure</topic><topic>Parietal Lobe - pathology</topic><topic>Pathology</topic><topic>Recombination, Genetic</topic><topic>Restriction Mapping</topic><topic>RNA</topic><topic>Rodents</topic><topic>Tay Sachs disease</topic><topic>Tay-Sachs Disease - enzymology</topic><topic>Tay-Sachs Disease - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamanaka, Shoji</creatorcontrib><creatorcontrib>Johnson, Mark D.</creatorcontrib><creatorcontrib>Grinberg, Alex</creatorcontrib><creatorcontrib>Westphal, Heiner</creatorcontrib><creatorcontrib>Crawley, Jacqueline N.</creatorcontrib><creatorcontrib>Tanike, Masako</creatorcontrib><creatorcontrib>Suzuki, Kinuko</creatorcontrib><creatorcontrib>Proia, Richard L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamanaka, Shoji</au><au>Johnson, Mark D.</au><au>Grinberg, Alex</au><au>Westphal, Heiner</au><au>Crawley, Jacqueline N.</au><au>Tanike, Masako</au><au>Suzuki, Kinuko</au><au>Proia, Richard L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1994-10-11</date><risdate>1994</risdate><volume>91</volume><issue>21</issue><spage>9975</spage><epage>9979</epage><pages>9975-9979</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Tay-Sachs disease, the prototype of the GM2gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system. Rapid mental and motor deterioration starting in the first year of life leads to death by 2-4 years of age. Through the targeted disruption of the mouse Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice displayed <1% of normal β-hexosaminidase A activity and accumulated GM2ganglioside in their central nervous system in an age-dependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At 3-5 months of age, the mutant mice showed no apparent defects in motor or memory function. These β-hexosaminidase A-deficient mice should be useful for devising strategies to introduce functional enzyme and genes into the central nervous system. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>7937929</pmid><doi>10.1073/pnas.91.21.9975</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals beta-N-Acetylhexosaminidases - deficiency beta-N-Acetylhexosaminidases - genetics Cell lines Central nervous system Child, Preschool Disease models Exploratory Behavior Gangliosides Genes Genetic Vectors Hexosaminidase A Humans Liver - enzymology Lysosomes - enzymology Medical research Mice Mice, Mutant Strains Microscopy, Electron Motor Activity Neurological disorders Neurons Neurons - pathology Neurons - ultrastructure Parietal Lobe - pathology Pathology Recombination, Genetic Restriction Mapping RNA Rodents Tay Sachs disease Tay-Sachs Disease - enzymology Tay-Sachs Disease - genetics |
| title | Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease |
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