{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T11:30:58Z","timestamp":1791804658949,"version":"4.3.4"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,6,8]]},"abstract":"<jats:p>\n                    Craniofrontonasal syndrome (CFNS) is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia and coronal craniosynostosis (fusion of the coronal sutures); in males, hypertelorism is the only typical manifestation. Here, we show that the classical female CFNS phenotype is caused by heterozygous loss-of-function mutations in\n                    <jats:italic>EFNB1<\/jats:italic>\n                    , which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases. In mice, the orthologous\n                    <jats:italic>Efnb1<\/jats:italic>\n                    gene is expressed in the frontonasal neural crest and demarcates the position of the future coronal suture. Although\n                    <jats:italic>EFNB1<\/jats:italic>\n                    is X-inactivated, we did not observe markedly skewed X-inactivation in either blood or cranial periosteum from females with CFNS, indicating that lack of ephrin-B1 does not compromise cell viability in these tissues. We propose that in heterozygous females, patchwork loss of ephrin-B1 disturbs tissue boundary formation at the developing coronal suture, whereas in males deficient in ephrin-B1, an alternative mechanism maintains the normal boundary. This is the only known mutation in the ephrin\/Eph receptor signaling system in humans and provides clues to the biogenesis of craniosynostosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402819101","type":"journal-article","created":{"date-parts":[[2004,5,27]],"date-time":"2004-05-27T20:13:27Z","timestamp":1085688807000},"page":"8652-8657","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":297,"title":["Mutations of ephrin-B1 (\n                    <i>EFNB1<\/i>\n                    ), a marker of tissue boundary formation, cause craniofrontonasal syndrome"],"prefix":"10.1073","volume":"101","author":[{"given":"Stephen R. F.","family":"Twigg","sequence":"first","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Kan","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Babbs","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena G.","family":"Bochukova","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Wall","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian M.","family":"Morriss-Kay","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew O. M.","family":"Wilkie","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; Center for Human and Animal Genetics, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Faculty of Life Science, Inner Mongolia University, Huhhot 010021, China; Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom; Department of Pediatrics and Child Health, University..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,5,27]]},"reference":[{"key":"e_1_3_2_1_2","first-page":"85","volume":"15","year":"1979","unstructured":"Cohen, M. M., Jr. (1979) Birth Defects Orig. Artic. Ser. 15, 85\u201389.","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"e_1_3_2_2_2","first-page":"75","volume":"15","year":"1979","unstructured":"Slover, R. & Sujansky, E. (1979) Birth Defects Orig. Artic. Ser. 15, 75\u201383.","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"e_1_3_2_3_2","first-page":"233","volume":"2","year":"1982","unstructured":"Reynolds, J. F., Haas, R. J., Edgerton, M. T. & Kelly, T. E. (1982) J. Craniofac. Genet. Dev. Biol. 2, 233\u2013238.7166597","journal-title":"J. Craniofac. Genet. Dev. Biol."},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/j.1399-0004.1986.tb00552.x","volume":"29","year":"1986","unstructured":"Sax, C. M. & Flannery, D. B. (1986) Clin. Genet. 29, 508\u2013515.3742856","journal-title":"Clin. Genet."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320270315"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.24.4.193"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0030-4220(88)90358-1"},{"key":"e_1_3_2_8_2","first-page":"361","volume":"6","year":"1995","unstructured":"Devriendt, K., Van Mol, C. & Fryns, J. P. (1995) Genet. Couns. (Geneva, Switzerland) 6, 361\u2013364.","journal-title":"Genet. Couns. (Geneva, Switzerland)"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960111)61:2<147::AID-AJMG8>3.0.CO;2-U"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0007-1226(97)91362-X"},{"key":"e_1_3_2_11_2","first-page":"823","volume":"33","year":"1981","unstructured":"Rollnick, B., Day, D., Tissot, R. & Kaye, C. (1981) Am. J. Hum. Genet. 33, 823\u2013826.7294029","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1159\/000071605"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1937"},{"key":"e_1_3_2_14_2","first-page":"2033","volume":"126","year":"1999","unstructured":"Holder, N. & Klein, R. (1999) Development (Cambridge, U.K.) 126, 2033\u20132044.","journal-title":"Development (Cambridge, U.K.)"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1996.0269"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(03)00198-9"},{"key":"e_1_3_2_17_2","first-page":"1229","volume":"51","year":"1992","unstructured":"Allen, R. C., Zoghbi, H. Y., Moseley, A. B., Rosenblatt, H. M. & Belmont, J. W. (1992) Am. J. Hum. Genet. 51, 1229\u20131239.1281384","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1119"},{"key":"e_1_3_2_19_2","unstructured":"Wilkinson D. G. (1992) in In Situ Hybridization: A Practical Approach ed. Wilkinson D. G. (IRL Oxford) pp. 75\u201383."},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00002-8"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/414933a"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81675-X"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0487"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.25.14440"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1086\/341123"},{"key":"e_1_3_2_26_2","unstructured":"Muenke M. & Wilkie A. O. M. (2000) in The Metabolic and Molecular Bases of Inherited Disease eds. Scriver C. R. Beaudet A. L. Sly W. S. & Valle D. (McGraw\u2013Hill New York) pp. 6117\u20136146."},{"key":"e_1_3_2_27_2","first-page":"5611","volume":"126","year":"1999","unstructured":"Iseki, S., Wilkie, A. O. M. & Morriss-Kay, G. M. (1999) Development (Cambridge, U.K.) 126, 5611\u20135620.","journal-title":"Development (Cambridge, U.K.)"},{"key":"e_1_3_2_28_2","first-page":"1845","volume":"127","year":"2000","unstructured":"Rice, D. P. C., \u00c5berg, T., Chan, Y., Tang, Z., Kettunen, P. J., Pakarinen, L., Maxson, R. E. Jr. & Thesleff, I. (2000) Development (Cambridge, U.K.) 127, 1845\u20131855.","journal-title":"Development (Cambridge, U.K.)"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80276-7"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/35058515"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1093703"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.2.724-734.2000"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(03)00395-2"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1171704"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0402819101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T09:24:59Z","timestamp":1705137899000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0402819101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,5,27]]},"references-count":34,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2004,6,8]]}},"alternative-id":["10.1073\/pnas.0402819101"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0402819101","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,5,27]]},"assertion":[{"value":"2004-03-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-05-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}