{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:17:09Z","timestamp":1785896229462,"version":"3.56.0"},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T00:00:00Z","timestamp":1416268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Nonsense mutations account for 5\u201370% of all genetic disorders. In the United States, nonsense mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">CLN<\/jats:styled-content>1\/<jats:styled-content style=\"fixed-case\">PPT<\/jats:styled-content>1<\/jats:italic> gene underlie &gt;40% of the patients with infantile neuronal ceroid lipofuscinosis (<jats:styled-content style=\"fixed-case\">INCL<\/jats:styled-content>), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of <jats:styled-content style=\"fixed-case\">INCL<\/jats:styled-content> carrying the most common <jats:italic>Ppt1<\/jats:italic> nonsense mutation (c.451C&gt;T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We knocked\u2010in c.451C&gt;T nonsense mutation in the <jats:italic>Ppt1<\/jats:italic> gene in C57 embryonic stem (<jats:styled-content style=\"fixed-case\">ES<\/jats:styled-content>) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted <jats:styled-content style=\"fixed-case\">ES<\/jats:styled-content> cells by electroporating <jats:italic>Cre<\/jats:italic>. Two independently targeted <jats:styled-content style=\"fixed-case\">ES<\/jats:styled-content> clones were injected into blastocysts to generate syngenic C57 knock\u2010in mice, obviating the necessity for extensive backcrossing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Generation of <jats:italic>Ppt1<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">KI<\/jats:styled-content> mice was confirmed by <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> sequencing, which showed the presence of c.451C&gt;T mutation in the <jats:italic>Ppt1<\/jats:italic> gene. These mice are viable and fertile, although they developed spasticity (a \u201cclasping\u201d phenotype) at a median age of 6\u00a0months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (<jats:styled-content style=\"fixed-case\">ERG<\/jats:styled-content>) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings show that <jats:italic>Ppt1<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">KI<\/jats:styled-content> mice reliably recapitulate <jats:styled-content style=\"fixed-case\">INCL<\/jats:styled-content> phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.144","type":"journal-article","created":{"date-parts":[[2014,11,18]],"date-time":"2014-11-18T07:55:36Z","timestamp":1416297336000},"page":"1006-1023","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Mice homozygous for c.451C&gt;T mutation in <i>Cln1<\/i> gene recapitulate <scp>INCL<\/scp> phenotype"],"prefix":"10.1002","volume":"1","author":[{"given":"Ashleigh","family":"Bouchelion","sequence":"first","affiliation":[{"name":"Program on Developmental Endocrinology and Genetics Section on Developmental Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Program on Developmental Endocrinology and Genetics Section on Developmental Genetics Eunice Kennedy\u2010Shriver National Institute of Child Health and Human Development Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichao","family":"Li","sequence":"additional","affiliation":[{"name":"Visual Function Core (HNW2\u2010L) National Eye Institute National Institutes of Health Bethesda Maryland 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