{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:00:22Z","timestamp":1791140422058,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,9,10]],"date-time":"2018-09-10T00:00:00Z","timestamp":1536537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["BRG 6180007"],"award-info":[{"award-number":["BRG 6180007"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:p>Split\u2010hand\/foot malformation (SHFM) is caused by mutations in <jats:italic>TP63<\/jats:italic>, <jats:italic>DLX5<\/jats:italic>, <jats:italic>DLX6<\/jats:italic>, <jats:italic>FGF8<\/jats:italic>, <jats:italic>FGFR1<\/jats:italic>, <jats:italic>WNT10B<\/jats:italic>, and <jats:italic>BHLHA9<\/jats:italic>. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM\u2010associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM\u2010related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM. Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf\u2010Bmp\u2010Msx signaling on apoptotic cell death. Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of <jats:italic>HOX<\/jats:italic> genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R. Disruption of canonical and non\u2010canonical Wnt signaling is involved in the pathogenesis of SHFM. Whatever the causative genes of SHFM are, the mutations seem to lead to dysregulation of Fgf8 in AER cells of the central parts of the hands and feet and disruption of Wnt\u2010Bmp\u2010Fgf signaling pathways in AER.<\/jats:p>","DOI":"10.1111\/cge.13434","type":"journal-article","created":{"date-parts":[[2018,8,13]],"date-time":"2018-08-13T06:25:55Z","timestamp":1534141555000},"page":"132-139","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Genetic regulatory pathways of split\u2010hand\/foot malformation"],"prefix":"10.1111","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-0881","authenticated-orcid":false,"given":"Piranit N.","family":"Kantaputra","sequence":"first","affiliation":[{"name":"Center of Excellence in Medical Genetics Research Chiang Mai University  Chiang Mai Thailand"},{"name":"Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry Faculty of Dentistry, Chiang Mai University  Chiang Mai Thailand"},{"name":"Dentaland Clinic  Chiang Mai Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology University of Michigan  Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn164"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.011759"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004468"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2016.167"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/323123"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2005.04.019"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100556"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.7"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000453350"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.166"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100409"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.10.012"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhsa.2010.12.033"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv514"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13152"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00163-6"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/19531"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/19539"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.027821"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13023"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10098"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.988402"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129.19.4371"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu096"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv151"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.8938"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3110-10.2011"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.4161\/org.4.2.5857"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1044903"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00285-9"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13218"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gep.2008.12.009"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2010.09.063"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1200421109"},{"key":"e_1_2_6_36_1","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1242\/dev.126.6.1211","article-title":"A. 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