{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:24:56Z","timestamp":1788305096575,"version":"build-2803163510"},"reference-count":70,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2016,8,4]],"date-time":"2016-08-04T00:00:00Z","timestamp":1470268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Fondecyt","award":["11090324"],"award-info":[{"award-number":["11090324"]}]},{"name":"Fondecyt","award":["11090105"],"award-info":[{"award-number":["11090105"]}]},{"name":"Fondecyt","award":["1120222"],"award-info":[{"award-number":["1120222"]}]},{"name":"Institute of Biomedical Sciences, Facultad de Medicina, Universidad de Chile","award":["1160518"],"award-info":[{"award-number":["1160518"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Orofacial clefts (OFCs) are common birth defects, which include\u00a0a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3\u2010hydroxy\u20103\u2010methyl\u2010glutaryl\u2010CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used zebrafish <jats:italic>hmgcrb<\/jats:italic> mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed <jats:italic>in situ<\/jats:italic> hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected\u2010siblings displayed a moderate phenotype, whereas early\u2010treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog\u2010signaling <jats:italic>gli1<\/jats:italic> in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin\u2010treated embryos.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results suggest that HMGCR loss\u2010of\u2010function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814\u2013830, 2016. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23546","type":"journal-article","created":{"date-parts":[[2016,8,4]],"date-time":"2016-08-04T09:42:23Z","timestamp":1470303743000},"page":"814-830","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of the 3\u2010hydroxy\u20103\u2010methyl\u2010glutaryl\u2010CoA reductase induces orofacial defects in zebrafish"],"prefix":"10.1002","volume":"106","author":[{"given":"Iskra A.","family":"Signore","sequence":"first","affiliation":[{"name":"Programa de Anatom\u00eda y Biolog\u00eda del Desarrollo, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile Santiago Chile"},{"name":"Instituto de Filosof\u00eda y Ciencias de la Complejidad (IFICC) Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Jerez","sequence":"additional","affiliation":[{"name":"Programa de Anatom\u00eda y Biolog\u00eda del Desarrollo, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Figueroa","sequence":"additional","affiliation":[{"name":"Programa de Anatom\u00eda y Biolog\u00eda del Desarrollo, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Suazo","sequence":"additional","affiliation":[{"name":"Institute for Research in Dental Sciences, Facultad de Odontolog\u00eda, Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Marcelain","sequence":"additional","affiliation":[{"name":"Programa de Gen\u00e9tica Humana, Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Cerda","sequence":"additional","affiliation":[{"name":"Programa de Biolog\u00eda Celular y Molecular, Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Colombo Flores","sequence":"additional","affiliation":[{"name":"Programa de Anatom\u00eda y Biolog\u00eda del Desarrollo, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad de Medicina, Universidad de Chile Santiago Chile"},{"name":"Servicio de Anatom\u00eda Patol\u00f3gica, Hospital Cl\u00ednico de la Universidad de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2012.02.002"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-06-03475.1994"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-387036-0.00005-0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.112.102442"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.3.022502.103031"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24256"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv507"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604751103"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02668"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1025302"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/383407a0"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1134"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602852103"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419596"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.12.023"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.08.134"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2933"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.080473"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.21.4113"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M611741200"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6365"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02281"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2012.11.024"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28988"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.41.110306.130315"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.01.016"},{"key":"e_1_2_7_28_1","first-page":"3940","article-title":"The muscle\u2010specific ubiquitin ligase atrogin\u20101\/MAFbx mediates statin\u2010induced muscle toxicity","volume":"117","author":"Hanai J","year":"2007","journal-title":"J Clin Invest"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120517"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059344"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00708"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-10-119"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1190304"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00364"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.12.029"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030302"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90628-4"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00369-5"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.09.013"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-3551-7"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-2760(00)00235-6"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.149"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307228200"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R009548"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80074-4"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.07.025"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1139740"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00023-1"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-9-59"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0014396"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2014.04.003"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.11.005"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2009.04.006"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002224"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22713"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2009.11.021"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.514"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.02.021"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(04)00032-2"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.4161\/org.7.4.18797"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/24871"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01943"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1080\/10520290701333558"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.03.520"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/35076601"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M700680200"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.26.061505.111311"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-013-8496-5"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2016.02.009"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002030308"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1127704"}],"container-title":["Birth Defects Research Part A: Clinical and Molecular Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.23546","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.23546","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdra.23546","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T14:43:49Z","timestamp":1695480229000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdra.23546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,4]]},"references-count":70,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["10.1002\/bdra.23546"],"URL":"https:\/\/doi.org\/10.1002\/bdra.23546","archive":["Portico"],"relation":{},"ISSN":["1542-0752","1542-0760"],"issn-type":[{"value":"1542-0752","type":"print"},{"value":"1542-0760","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,4]]}}}