{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:44:12Z","timestamp":1791121452223,"version":"4.1.0"},"reference-count":89,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2002,8,27]],"date-time":"2002-08-27T00:00:00Z","timestamp":1030406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am. J. Med. Genet."],"published-print":{"date-parts":[[2002,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Fibroblast growth factors (FGFs) comprise a family of 22 distinct proteins with pleiotropic signaling functions in development and homeostasis. These functions are mediated principally by four fibroblast growth factor receptors (FGFRs), members of the receptor tyrosine kinase family, with heparin glycosaminoglycan as an important cofactor. Developmental studies in chick and mouse highlight the critical role of FGF\u2010receptor signaling in multiple phases of limb development, including the positioning of the limb buds, the maintenance of limb bud outgrowth, the detailed patterning of the limb elements, and the growth of the long bones. Corroborating these important roles, mutations of two members of the FGFR family (<jats:italic>FGFR1<\/jats:italic> and <jats:italic>FGFR2<\/jats:italic>) are associated with human disorders of limb patterning; in addition, mutations of <jats:italic>FGFR3<\/jats:italic> and <jats:italic>FGF23<\/jats:italic> affect growth of the limb bones. Analysis of <jats:italic>FGFR2<\/jats:italic> mutations in particular reveals a complex pattern of genotype\/phenotype correlation, which will be reviewed in detail. Circumstantial evidence suggests that the more severe patterning abnormalities are mediated by illegitimate paracrine signaling in the mesoderm, mediated by FGF10 or by a related FGF, and this is beginning to gain some experimental support. A further test of this hypothesis is provided by a unique family segregating two <jats:italic>FGFR2<\/jats:italic> mutations in <jats:italic>cis<\/jats:italic> (S252L; A315S), in which severe syndactyly occurs in the absence of the craniosynostosis that typically accompanies <jats:italic>FGFR2<\/jats:italic> mutations. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.10775","type":"journal-article","created":{"date-parts":[[2002,10,9]],"date-time":"2002-10-09T05:01:24Z","timestamp":1034139684000},"page":"266-278","source":"Crossref","is-referenced-by-count":162,"title":["FGFs, their receptors, and human limb malformations: Clinical and molecular correlations"],"prefix":"10.1002","volume":"112","author":[{"given":"Andrew O.M.","family":"Wilkie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susannah J.","family":"Patey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010hsin","family":"Kan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ans M.W.","family":"van den Ouweland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben C.J.","family":"Hamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2002,8,27]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/81664"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.9.1475"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990702)85:1<53::AID-AJMG10>3.0.CO;2-F"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/316892"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.4.2205"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1271"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320470509"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320570119"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90352-6"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00006120"},{"key":"e_1_2_6_12_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1242\/dev.127.3.483","article-title":"An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal\u2010epithelial signaling during mouse organogenesis","volume":"127","author":"De Moerlooze L","year":"2000","journal-title":"Development"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.9.5106"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(98)00133-6"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1997.8553"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050348"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.35.9.705"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.121183798"},{"key":"e_1_2_6_19_1","first-page":"109","article-title":"Pfeiffer syndrome is not caused by haploinsufficient mutations of FGFR2","volume":"20","author":"Johnson D","year":"2000","journal-title":"J Cranio Genet Dev Biol"},{"key":"e_1_2_6_20_1","first-page":"1","volume-title":"Advances in cancer research","author":"Johnson DE","year":"1993"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200499"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1086\/338758"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00285-9"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M903271199"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980401)76:4<362::AID-AJMG15>3.0.CO;2-M"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1999.90.3.0443"},{"key":"e_1_2_6_27_1","first-page":"346","article-title":"Fibroblast growth factor receptor 1 signaling during limb and sternum development","volume":"69","author":"Lalioti MD","year":"2001","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107381200"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2544996"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/82609"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.965602"},{"key":"e_1_2_6_32_1","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1242\/dev.128.13.2451","article-title":"Evidence for a role of protein kinase C in FGF signal transduction in the developing chick limb bud","volume":"128","author":"Lu H\u2010C","year":"2001","journal-title":"Development"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.11.1571"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.20.3156"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80131-2"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.11.2075"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/82601"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2012.4"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1194-269"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006534-199911000-00001"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19971128)73:1<61::AID-AJMG12>3.0.CO;2-P"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001665-199803000-00015"},{"key":"e_1_2_6_43_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1080\/15513819809168795","article-title":"FGF signaling in skeletal development","volume":"18","author":"Naski MC","year":"1999","journal-title":"Pediar Pathol Mol Med"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.44.26037"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/361068a0"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.965702"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1995.1572"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990716)85:2<160::AID-AJMG11>3.0.CO;2-R"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.1.137"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1086\/302245"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-1878(200002)22:2<108::AID-BIES2>3.0.CO;2-M"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2001-2-3-reviews3005"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.25.15292"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.12.15.2332"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19970808)71:2<243::AID-AJMG27>3.0.CO;2-D"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.35.8.677"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/35039551"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00447500"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980123)75:3<245::AID-AJMG3>3.0.CO;2-P"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80051-3"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80851-X"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.52.35250"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(98)70186-6"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.1.26"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.0144"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.8.4567"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960315)62:2<184::AID-AJMG13>3.0.CO;2-K"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20000703)93:1<22::AID-AJMG5>3.0.CO;2-U"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0295-173"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980123)75:3<252::AID-AJMG4>3.0.CO;2-S"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/4.3.323"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/5096"},{"key":"e_1_2_6_73_1","first-page":"923","article-title":"Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome","volume":"58","author":"Slaney SF","year":"1996","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.49"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/75644"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(00)00220-3"},{"key":"e_1_2_6_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2001.tb00811.x"},{"key":"e_1_2_6_78_1","first-page":"183","article-title":"Pfeiffer syndrome caused by haploinsufficient mutation of FGFR2","volume":"19","author":"Tsukuno M","year":"1999","journal-title":"J Cranio Genet Dev Biol"},{"key":"e_1_2_6_79_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.21.1.23"},{"key":"e_1_2_6_80_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2000.570208.x"},{"key":"e_1_2_6_81_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi981758m"},{"key":"e_1_2_6_82_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.19.3867"},{"key":"e_1_2_6_83_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6332"},{"key":"e_1_2_6_84_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980707)78:3<274::AID-AJMG14>3.0.CO;2-C"},{"key":"e_1_2_6_85_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.10.1647"},{"key":"e_1_2_6_86_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004410051264"},{"key":"e_1_2_6_87_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19971031)72:3<354::AID-AJMG21>3.0.CO;2-R"},{"key":"e_1_2_6_88_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.081082498"},{"key":"e_1_2_6_89_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.26.14536"},{"key":"e_1_2_6_90_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.13.2001"}],"container-title":["American Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajmg.10775","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.10775","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,18]],"date-time":"2023-11-18T00:44:54Z","timestamp":1700268294000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.10775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,8,27]]},"references-count":89,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2002,10,15]]}},"alternative-id":["10.1002\/ajmg.10775"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.10775","archive":["Portico"],"relation":{},"ISSN":["0148-7299","1096-8628"],"issn-type":[{"value":"0148-7299","type":"print"},{"value":"1096-8628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,8,27]]}}}