{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:06:02Z","timestamp":1790892362847,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2008,11,5]],"date-time":"2008-11-05T00:00:00Z","timestamp":1225843200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL16237"],"award-info":[{"award-number":["HL16237"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA06927"],"award-info":[{"award-number":["CA06927"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2009,3]]},"abstract":"<jats:p>\n                    Untreated cystathionine \u03b2\u2010synthase (CBS) deficiency in humans is characterized by extremely elevated plasma total homocysteine (tHcy&gt;200 \u00b5\u039c), with thrombosis as the major cause of morbidity. Treatment with vitamins and diet leads to a dramatic reduction in thrombotic events, even though patients often still have severe elevations in tHcy (&gt;80 \u00b5\u039c). To understand the difference between extreme and severe hyperhomocysteinemia, we have examined two mouse models of CBS deficiency:\n                    <jats:italic>Tg\u2010hCBS Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice, with a mean serum tHcy of 169 \u00b5\u039c, and\n                    <jats:italic>Tg\u2010I278T Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice, with a mean tHcy of 296 \u00b5\u039c. Only\n                    <jats:italic>Tg\u2010I278T Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    animals exhibited strong biological phenotypes, including facial alopecia, osteoporosis, endoplasmic reticulum (ER) stress in the liver and kidney, and a 20% reduction in mean survival time. Metabolic profiling of serum and liver reveals that\n                    <jats:italic>Tg\u2010I278T Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice have significantly elevated levels of free oxidized homocysteine but not protein\u2010bound homocysteine in serum and elevation of all forms of homocysteine and S\u2010adenosyl\u2010homocysteine in the liver compared to\n                    <jats:italic>Tg\u2010hCBS Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice. RNA profiling of livers indicate that\n                    <jats:italic>Tg\u2010I278T Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    and\n                    <jats:italic>Tg\u2010hCBS Cbs<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice have unique gene signatures, with minimal overlap. Our results indicate that there is a clear pathogenic threshold effect for tHcy and bring into question the idea that mild elevations in tHcy are directly pathogenic.\u2014 Gupta, S., Kuhnisch, J., Mustafa, A., Lhotak, S., Schlachterman, A., Slifker, M. J., Klein\u2010Szanto, A., High, K. A., Austin, R. C., Kruger, W. D. Mouse models of cystathionine \u03b2\u2010synthase deficiency reveal significant threshold effects of hyperhomocysteinemia.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    23, 883\u2013893 (2009)\n                  <\/jats:p>","DOI":"10.1096\/fj.08-120584","type":"journal-article","created":{"date-parts":[[2008,11,5]],"date-time":"2008-11-05T21:10:05Z","timestamp":1225919405000},"page":"883-893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":105,"title":["Mouse models of cystathionine \u03b2\u2010synthase deficiency reveal significant threshold effects of hyperhomocysteinemia"],"prefix":"10.1096","volume":"23","author":[{"given":"Sapna","family":"Gupta","sequence":"first","affiliation":[{"name":"Division of Population Science Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jirko","family":"K\u00fchnisch","sequence":"additional","affiliation":[{"name":"Institute for Medical Genetics Charit\u00e8 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aladdin","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Division of Population Science Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarka","family":"Lhotak","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Schlachterman","sequence":"additional","affiliation":[{"name":"Division of Hematology The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Slifker","sequence":"additional","affiliation":[{"name":"Biostatistics Facility Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Klein\u2010Szanto","sequence":"additional","affiliation":[{"name":"Division of Population Science Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"High","sequence":"additional","affiliation":[{"name":"Division of Hematology The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Medicine McMaster University Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren D.","family":"Kruger","sequence":"additional","affiliation":[{"name":"Division of Population Science Fox Chase Cancer Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,11,5]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.49.1.31"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92407-8"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032546"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011613"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2005.7.813"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/44.8.1833"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10290"},{"key":"e_1_2_6_9_1","first-page":"1","article-title":"The natural history of homocystinuria due to cystathionine beta\u2010synthase deficiency","volume":"37","author":"Mudd S. H.","year":"1985","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1005373209964"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2000-8100"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/hq1201.100225"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.5.1585"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000129182.46440.4a"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1999)13:5<362::AID-HUMU4>3.0.CO;2-K"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi224"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32878"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20052444"},{"key":"e_1_2_6_19_1","first-page":"3","article-title":"Linear models and empirical bayes methods for assessing differential expression in microarray experiments","author":"Smyth G. K.","year":"2004","journal-title":"Stat. Appl. Genet. Mol. Biol."},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-10-r80"},{"key":"e_1_2_6_21_1","first-page":"2007","volume-title":"The Metabolic Basis of Inherited Disease","author":"Mudd S. H.","year":"2001"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90086-9"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212897200"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.a.20082"},{"key":"e_1_2_6_25_1","first-page":"48","article-title":"Cystathionine beta\u2010synthase p.S466L mutation causes hyperhomocysteinemia in mice","volume":"10","author":"Gupta S.","year":"2008","journal-title":"Hum. Mutat."},{"key":"e_1_2_6_26_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ar.a.20145","article-title":"Cystathionine beta synthase deficiency affects mouse endochondral ossification","volume":"282","author":"Robert K.","year":"2005","journal-title":"Anat. Rec. A Discov. Mol. Cell. Evol. Biol."},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(03)00276-2"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11596"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1809"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi001088w"},{"key":"e_1_2_6_31_1","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1093\/ajcn\/34.12.2619","article-title":"Plasma cyst(e)ine in homocyst(e)inemia","volume":"34","author":"Malloy M. H.","year":"1981","journal-title":"Am. J. Clin. Nutr."},{"key":"e_1_2_6_32_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0031-6997(25)00053-5","article-title":"Pharmacological and biochemical aspects of S\u2010adenosylhomocysteine and S\u2010adenosylhomocysteine hydrolase","volume":"34","author":"Ueland P. M.","year":"1982","journal-title":"Pharmacol. Rev."},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(94)90004-3"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa055227"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.299.17.2027"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa060900"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00105-9"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.44.31139"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.11.040"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.3.959.415k20_959_967"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708598200"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2007.05.002"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232588799"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.08-120584","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.08-120584","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.08-120584","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T16:06:28Z","timestamp":1761667588000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.08-120584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,5]]},"references-count":42,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,3]]}},"alternative-id":["10.1096\/fj.08-120584"],"URL":"https:\/\/doi.org\/10.1096\/fj.08-120584","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,11,5]]},"assertion":[{"value":"2008-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-10-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-11-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}