{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:54:14Z","timestamp":1791071654051,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,12,5]],"date-time":"2012-12-05T00:00:00Z","timestamp":1354665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited \u223c86 kb FREM1 deletion that affects the expression of FREM1's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N-ethyl-N-nitrosourea -derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1eyes2 mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1eyes2 embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.<\/jats:p>","DOI":"10.1093\/hmg\/dds507","type":"journal-article","created":{"date-parts":[[2012,12,8]],"date-time":"2012-12-08T07:43:31Z","timestamp":1354952611000},"page":"1026-1038","source":"Crossref","is-referenced-by-count":43,"title":["Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice"],"prefix":"10.1093","volume":"22","author":[{"given":"Tyler F","family":"Beck","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Veenma","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery"},{"name":"Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GJ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg A","family":"Shchelochkov","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bum Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitisha P","family":"Zaveri","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande","family":"van Bever","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GJ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunju","family":"Choi","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine and Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannie","family":"Douben","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GJ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry K","family":"Bertin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragna I","family":"Patel","sequence":"additional","affiliation":[{"name":"Institute for Genetic Medicine and Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"},{"name":"Howard Hughes Medical Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Tibboel","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"de Klein","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3015 GJ, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Stockton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica J","family":"Justice","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryl A","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics"},{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,12,5]]},"reference":[{"key":"2020020502154328100_DDS507C1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s00383-009-2425-8","article-title":"Can we improve outcome of congenital diaphragmatic hernia?","volume":"25","author":"van den Hout","year":"2009","journal-title":"Pediatr. 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