{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:40:55Z","timestamp":1791189655582,"version":"4.1.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,3,24]]},"abstract":"<jats:p>\n                    Noonan syndrome (NS), the most common single-gene cause of congenital heart disease, is an autosomal dominant disorder that also features proportionate short stature, facial abnormalities, and an increased risk of myeloproliferative disease. Germline-activating mutations in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    , which encodes the protein tyrosine phosphatase SHP2, cause about half of NS cases; other causative alleles include\n                    <jats:italic>KRAS<\/jats:italic>\n                    ,\n                    <jats:italic>SOS1<\/jats:italic>\n                    , and\n                    <jats:italic>RAF1<\/jats:italic>\n                    mutants. We showed previously that knock-in mice bearing the NS mutant\n                    <jats:italic>\n                      Ptpn11\n                      <jats:sup>D61G<\/jats:sup>\n                    <\/jats:italic>\n                    on a mixed 129S4\/SvJae X C57BL6\/J background exhibit all major NS features, including a variety of cardiac defects, with variable penetrance. However, the cellular and molecular mechanisms underlying NS cardiac defects and whether genetic background and\/or the specific NS mutation contribute to the NS phenotype remained unclear. Here, using an inducible knock-in approach, we show that all cardiac defects in NS result from mutant Shp2 expression in the endocardium, not in the myocardium or neural crest. Furthermore, the penetrance of NS defects is affected by genetic background and the specific\n                    <jats:italic>Ptpn11<\/jats:italic>\n                    allele. Finally, ex vivo assays and pharmacological approaches show that NS mutants cause cardiac valve defects by increasing Erk MAPK activation, probably downstream of ErbB family receptor tyrosine kinases, extending the interval during which cardiac endocardial cells undergo endocardial-mesenchymal transformation. Our data provide a mechanistic underpinning for the cardiac defects in this disorder.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0810053106","type":"journal-article","created":{"date-parts":[[2009,2,27]],"date-time":"2009-02-27T21:11:49Z","timestamp":1235769109000},"page":"4736-4741","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":121,"title":["Noonan syndrome cardiac defects are caused by\n                    <i>PTPN11<\/i>\n                    acting in endocardium to enhance endocardial-mesenchymal transformation"],"prefix":"10.1073","volume":"106","author":[{"given":"Toshiyuki","family":"Araki","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8\u2013355, Toronto, ON, Canada M5G1L7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8\u2013355, Toronto, ON, Canada M5G1L7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Newbigging","sequence":"additional","affiliation":[{"name":"Pathology Core, Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, ON, Canada M5T 3H7;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Pathology Core, Centre for Modeling Human Disease, Toronto Centre for Phenogenomics, Toronto, ON, Canada M5T 3H7;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick T.","family":"Bronson","sequence":"additional","affiliation":[{"name":"Rodent Histopathology Core, Harvard Medical School, Goldenson 141, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Neel","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;"},{"name":"Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, 101 College Street, TMDT8\u2013355, Toronto, ON, Canada M5G1L7"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,3,24]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1177\/000992289403300907"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.6.080604.162305"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-008-9126-y"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(03)00091-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0306-283"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20748"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000141146.95728.da"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.77.2.211"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.08.058"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(03)00099-X"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1084"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504699200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30756"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1059"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805239105"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1156"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.042390499"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000141429.13560.cb"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.136.1.193"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm742"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.20.5896"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1086\/340847"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2003.11.032"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30270"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.22.4359"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000186194.06514.b0"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M702881200"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/39593"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2003.09.012"},{"key":"e_1_3_4_30_2","first-page":"1385","article-title":"Erlotinib OSI\/Roche\/Genentech","volume":"3","author":"Kim TE","year":"2002","unstructured":"TE Kim, JR Murren, Erlotinib OSI\/Roche\/Genentech. Current Opinion in Investigational Drugs 3, 1385\u20131395 (2002).","journal-title":"Current Opinion in Investigational Drugs"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3493"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02519"},{"key":"e_1_3_4_33_2","article-title":"Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis","author":"Chan G","year":"2009","unstructured":"G Chan, et al., Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. Blood, in press. 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