{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:25:32Z","timestamp":1781105132871,"version":"3.54.1"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,1,16]]},"abstract":"<jats:p>\n                    Hereditary tyrosinemia type 1 (HT1) is a severe autosomal recessive\n metabolic disease associated with point mutations in the human\n fumarylacetoacetate hydrolase (\n                    <jats:italic>FAH<\/jats:italic>\n                    ) gene that disrupt\n tyrosine catabolism. An acute form of HT1 results in death during the\n first months of life because of hepatic failure, whereas a chronic form\n leads to gradual development of liver disease often accompanied by\n renal dysfunction, childhood rickets, neurological crisis, and\n hepatocellular carcinoma. Mice homozygous for certain chromosome 7\n deletions of the albino\n                    <jats:italic>Tyr<\/jats:italic>\n                    ;\n                    <jats:italic>c<\/jats:italic>\n                    locus that\n also include\n                    <jats:italic>Fah<\/jats:italic>\n                    die perinatally as a result of liver\n dysfunction and exhibit a complex syndrome characterized by structural\n abnormalities and alterations in gene expression in the liver and\n kidney. Here we report that two independent, postnatally lethal\n mutations induced by\n                    <jats:italic>N<\/jats:italic>\n                    -ethyl-\n                    <jats:italic>N<\/jats:italic>\n                    -nitrosourea and mapped near\n                    <jats:italic>Tyr<\/jats:italic>\n                    are alleles of\n                    <jats:italic>Fah<\/jats:italic>\n                    . The\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>6287SB<\/jats:sup>\n                    allele is a missense mutation in\n exon 6, and\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>5961SB<\/jats:sup>\n                    is a splice mutation\n causing loss of exon 7, a subsequent frameshift in the resulting mRNA,\n and a severe reduction of\n                    <jats:italic>Fah<\/jats:italic>\n                    mRNA levels. Increased\n levels of the diagnostic metabolite succinylacetone in the urine of the\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>6287SB<\/jats:sup>\n                    and\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>5961SB<\/jats:sup>\n                    mutants indicate that these\n mutations cause a decrease in Fah enzymatic activity. Thus, the\n neonatal phenotype present in both mutants is due to a deficiency in\n Fah caused by a point mutation, and we propose\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>5961SB<\/jats:sup>\n                    and\n                    <jats:italic>Fah<\/jats:italic>\n                    <jats:sup>6287SB<\/jats:sup>\n                    as mouse models for acute and\n chronic forms of human HT1, respectively.\n                  <\/jats:p>","DOI":"10.1073\/pnas.98.2.641","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:45:09Z","timestamp":1027680309000},"page":"641-645","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":55,"title":["Point mutations in the murine fumarylacetoacetate hydrolase gene: Animal models for the human genetic disorder hereditary tyrosinemia type 1"],"prefix":"10.1073","volume":"98","author":[{"given":"Jennifer L.","family":"Aponte","sequence":"first","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary A.","family":"Sega","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loren J.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhu S.","family":"Dhar","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine M.","family":"Withrow","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. Box 2009, Oak Ridge, TN 37831-8077"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene M.","family":"Rinchik","sequence":"additional","affiliation":[{"name":"Division of Biology, University of Tennessee, Knoxville, TN\r 37996-0910; and Life Sciences Division, Oak Ridge\r National Laboratory, P.O. 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