{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:16:49Z","timestamp":1789579009879,"version":"build-2803163510"},"reference-count":49,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5405","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1999,2,19]]},"abstract":"<jats:p>\n            Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified\n            <jats:italic>Ufd1<\/jats:italic>\n            , which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse\n            <jats:italic>Ufd1<\/jats:italic>\n            was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human\n            <jats:italic>UFD1L<\/jats:italic>\n            gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of\n            <jats:italic>UFD1L<\/jats:italic>\n            was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that\n            <jats:italic>UFD1L<\/jats:italic>\n            haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.\n          <\/jats:p>","DOI":"10.1126\/science.283.5405.1158","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:40:50Z","timestamp":1027762850000},"page":"1158-1161","source":"Crossref","is-referenced-by-count":236,"title":["A Molecular Pathway Revealing a Genetic Basis for Human Cardiac and Craniofacial Defects"],"prefix":"10.1126","volume":"283","author":[{"given":"Hiroyuki","family":"Yamagishi","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, Division of Cardiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidu","family":"Garg","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Division of Cardiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rumiko","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffani","family":"Thomas","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Division of Cardiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Division of Cardiology, and"},{"name":"Molecular Biology and Oncology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Room NA8.124, Dallas, TX 75235\u20139148, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/BF00801907","volume":"16","author":"Hoffman J. I. E.","year":"1995","unstructured":"Hoffman J. I. E., Pediatr. Cardiol. 16, 103 (1995).","journal-title":"Pediatr. Cardiol."},{"key":"e_1_3_1_3_2","unstructured":"D. C. Fyler in Nadas' Pediatric Cardiology Trends A. S. Nadas and D. C. Fyler Eds. (Hanley & Belfus Philadelphia 1992) pp. 273\u2013280;"},{"key":"e_1_3_1_3_3","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0002-9149(86)90256-0","volume":"56","author":"Van Mierop L. H. S.","year":"1986","unstructured":"Van Mierop L. H. S., Kutsche L. M., Am. J. Cardiol. 56, 133 (1986).","journal-title":"Am. J. Cardiol."},{"key":"e_1_3_1_4_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/1050-1738(93)90023-Y","volume":"3","author":"Kirby M. L.","year":"1993","unstructured":"Kirby M. L., Trends Cardiovasc. Med. 3, 18 (1993).","journal-title":"Trends Cardiovasc. Med."},{"key":"e_1_3_1_5_2","first-page":"924","volume":"50","author":"Driscoll D. A.","year":"1992","unstructured":"Driscoll D. A., et al., Am. J. 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Cardiol."},{"key":"e_1_3_1_6_4","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0002-9149(97)00401-3","volume":"80","author":"Lewin M. B.","year":"1997","unstructured":"Lewin M. B., et al., Am. J. Cardiol. 80, 493 (1997).","journal-title":"Am. J. Cardiol."},{"key":"e_1_3_1_7_2","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1161\/01.CIR.82.2.332","volume":"82","author":"Kirby M. L.","year":"1990","unstructured":"Kirby M. L., Waldo K. L., Circulation 82, 332 (1990).","journal-title":"Circulation"},{"key":"e_1_3_1_8_2","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1093\/hmg\/5.6.789","volume":"5","author":"Gong W.","year":"1996","unstructured":"Gong W., et al., Hum. Mol. Genet. 5, 789 (1996);","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_8_3","first-page":"7","volume":"59","author":"Dallapiccola B.","year":"1996","unstructured":"Dallapiccola B., Pizzuti A., Novelli G., Am. J. Hum. Genet. 59, 7 (1996);","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_8_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1101\/gr.7.1.17","volume":"7","author":"Galili N.","year":"1997","unstructured":"Galili N., et al., Genome Res. 7, 17 (1997);","journal-title":"Genome Res."},{"key":"e_1_3_1_8_5","doi-asserted-by":"crossref","first-page":"14608","DOI":"10.1073\/pnas.94.26.14608","volume":"94","author":"Puech A.","year":"1997","unstructured":"Puech A., et al., Proc. Natl. Acad. Sci. U.S.A. 94, 14608 (1997);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_8_6","doi-asserted-by":"crossref","unstructured":"; B. S. Emanuel M. L. Budarf P. J. Scambler in Heart Development R. P. Harvey and N. Rosenthal Eds. (Academic Press San Diego 1998) pp. 463\u2013478.","DOI":"10.1016\/B978-012329860-7\/50028-3"},{"key":"e_1_3_1_9_2","first-page":"A10","volume":"55","author":"Li M.","year":"1994","unstructured":"Li M., et al., Am. J. Med. Genet. 55, A10 (1994);","journal-title":"Am. J. Med. 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Invest."},{"key":"e_1_3_1_13_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1242\/dev.125.5.813","volume":"125","author":"Clouthier D.","year":"1998","unstructured":"Clouthier D., et al., Development 125, 813 (1998).","journal-title":"Development"},{"key":"e_1_3_1_14_2","unstructured":"Total RNA (1 \u03bcg) from wild-type and dHAND -null E9.5 hearts was treated with deoxyribonuclease and used to generate cDNA by the SMART cDNA synthesis kit (Clontech). PCR-Select (Clontech) was used for subtractive hybridization. Briefly two pools of Rsa I\u2013digested wild-type cDNA were used as tester and ligated to unique adapters. Rsa I\u2013digested dHAND -null cDNA was used as driver without adapters. Hybridization of the tester population with excess driver and amplification of subtracted species with the two unique adapters in the tester cDNA produced a pool of PCR-amplified fragments theoretically present in wild-type but not dHAND mutant RNA. The PCR products were cloned and sequenced."},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.29.17442"},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/hmg\/6.2.259","volume":"6","author":"Pizzuti A.","year":"1997","unstructured":"Pizzuti A., et al., Hum. Mol. Genet. 6, 259 (1997);","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_16_3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/S0167-4781(97)00211-X","volume":"1396","author":"Novelli G.","year":"1998","unstructured":"Novelli G., et al., Biochim. Biophys. Acta 1396, 158 (1998);","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_3_1_16_4","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1159\/000134592","volume":"77","author":"Botta A.","year":"1997","unstructured":"Botta A., et al., Cytogenet. Cell Genet. 77, 264 (1997).","journal-title":"Cytogenet. Cell Genet."},{"key":"e_1_3_1_17_2","unstructured":"Total RNA was purified from hearts of wild-type and dHAND -null embryos at E9.5 and used for cDNA synthesis. PCR analysis was performed with oligonucleotides specific for mouse Ufd1 (upper 5\u2032-GGAGAAAGGAGGGAAGATAA-3\u2032; lower 5\u2032-CGAAGTAGGAGAAGTTGGAA-3\u2032) or mouse Cdc45 (upper 5\u2032-ACCACTTCATCCAGGCTCTC-3\u2032; lower 5\u2032-GGTGCTTTCTGCTGCCTTCT-3\u2032) under the following conditions: 94\u00b0C for 5 min; 94\u00b0C for 1 min 52\u00b0C for 1 min and 72\u00b0C for 1 min; and 72\u00b0C for 7 min. PCR products were analyzed by agarose gel electrophoresis after serial cycles in the linear range of amplification. RNA loading was controlled for by amplification of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase ( G3PDH ) . Negative controls were performed for each sample using non\u2013reverse-transcribed RNA. A Southern blot of the samples was hybridized for UFD1L or G3PDH."},{"key":"e_1_3_1_18_2","unstructured":"Human metaphase chromosome slides were prepared from Epstein-Barr virus\u2013transformed lymphoblastoid cell lines or peripheral blood. Slides were hybridized with a genomic clone encompassing UFD1L that had been obtained by screening a human P1 artificial chromosome library with UFD1L -specific primers. FISH analysis was performed according to R. Matsuoka et al. [ Hum. Genet. 103 70 (1998)]. Patients with 22q11 deletion had been characterized by FISH using the N25 (Oncor) marker that does not encompass UFD1L."},{"key":"e_1_3_1_19_2","unstructured":"Whole-mount in situ hybridizations were performed with digoxygenin-labeled antisense riboprobes synthesized from the 700-bp open reading frame and the 250-bp 3\u2032 untranslated region of mouse UFD1L cDNA (9). Embryos were photographed with and without clearing in benzyl benzoate:methyl salicylate (1:1). For histologic analysis stained embryos were embedded in paraffin after fixation. Transverse and sagittal sections were made at 8-\u03bcm intervals throughout the embryos."},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6844926"},{"key":"e_1_3_1_21_2","first-page":"1069","volume":"272","author":"Olson E. N.","year":"1996","unstructured":"Olson E. N., Srivastava D., ibid. 272, 1069 (1996);","journal-title":"ibid."},{"key":"e_1_3_1_21_3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1161\/01.RES.77.2.211","volume":"77","author":"Kirby M. L.","year":"1995","unstructured":"Kirby M. L., Waldo K. L., Circ. Res. 77, 211 (1995).","journal-title":"Circ. Res."},{"key":"e_1_3_1_22_2","unstructured":"A research protocol for human studies was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. Informed consent was obtained from the parents for collection of blood and thymic tissue. Genomic DNA was obtained from 10 individuals at Children's Hospital Medical Center of Dallas with normal karyotype and negative FISH for 22q11 deletion who had cardiac or craniofacial defects or both typical of 22q11 deletion; DNA from 100 control individuals with normal karyotype was also obtained. Genomic DNA extracted from human blood or thymic tissue (QIAamp blood kit QIAGEN) was digested with Eco RI or Hind III transferred to nylon membranes and hybridized to 32 P-labeled UFD1L or CDC45 cDNA."},{"key":"e_1_3_1_23_2","unstructured":"Thymic tissue was collected from patients who were undergoing surgical repair of CHD and total RNA was extracted and used for cDNA synthesis. Northern analysis was performed on 20 \u03bcg of total thymic RNA and hybridized to a UFD1L cDNA probe. HIRA - and CDC45 -specific amplimers were used to amplify the respective cDNAs. HIRA amplimers were: upper 5\u2032-GACGGCTCTGTGGCATTCCT-3\u2032; lower 5\u2032-GCCATCTGCTGTCCGAGTCT-3\u2032. CDC45 amplimers were: upper 5\u2032-GCCTTGTTCCAGTGTGACCA-3\u2032; lower 5\u2032-GTTCTCCTCATCCTCGTTCC-3\u2032."},{"key":"e_1_3_1_24_2","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/ng0896-458","volume":"13","author":"Daw S. C.","year":"1996","unstructured":"Daw S. C., et al., Nature Genet. 13, 458 (1996).","journal-title":"Nature Genet."},{"key":"e_1_3_1_25_2","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/hmg\/6.2.247","volume":"6","author":"Wilming L. G.","year":"1997","unstructured":"Wilming L. G., et al., Hum. Mol. Genet. 6, 247 (1997);","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_25_3","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/1739","volume":"20","author":"Magnaghi P.","year":"1998","unstructured":"Magnaghi P., et al., Nature Genet. 20, 74 (1998).","journal-title":"Nature Genet."},{"key":"e_1_3_1_26_2","unstructured":"H. Yamagishi V. Garg D. Srivastava unpublished observations."},{"key":"e_1_3_1_27_2","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1101\/gr.8.8.834","volume":"8","author":"McKie J.","year":"1998","unstructured":"McKie J., et al., Genome Res. 8, 834 (1998).","journal-title":"Genome Res."},{"key":"e_1_3_1_28_2","first-page":"A193","volume":"63","author":"Shaikh T. H.","year":"1998","unstructured":"Shaikh T. H., et al., Am. J. Hum. Genet. 63, A193 (1998).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90384-3"},{"key":"e_1_3_1_29_3","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1074\/jbc.273.3.1409","volume":"273","author":"Sears C.","year":"1998","unstructured":"Sears C., Olesen J., Rubin D., Finley D., Maniatis T., J. Biol. Chem. 273, 1409 (1998).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_30_2","doi-asserted-by":"crossref","first-page":"6121","DOI":"10.1074\/jbc.273.11.6121","volume":"273","author":"Monney L.","year":"1998","unstructured":"Monney L., et al., J. Biol. Chem. 273, 6121 (1998).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_31_2","unstructured":"We thank R. Schultz and A. Bowcock for helpful discussions and assistance with genetic analyses members of the pediatric cardiology and cardiothoracic surgery divisions for assistance with tissue collection other members of the Srivastava laboratory for critical discussion J. L. Goldstein M. S. Brown E. N. Olson and H. H. Hobbs for critical review of this manuscript and J. Page for manuscript preparation. Supported by grants to D.S. from NIH (R01HL57181-01) and March of Dimes."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.283.5405.1158","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T03:39:08Z","timestamp":1705117148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.283.5405.1158"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,2,19]]},"references-count":49,"journal-issue":{"issue":"5405","published-print":{"date-parts":[[1999,2,19]]}},"alternative-id":["10.1126\/science.283.5405.1158"],"URL":"https:\/\/doi.org\/10.1126\/science.283.5405.1158","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,2,19]]}}}