{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:01:40Z","timestamp":1790074900109,"version":"4.0.1"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2004,9,14]]},"abstract":"<jats:p>\n                    Fraser syndrome is a rare recessive disorder characterized by cryptophthalmos, syndactyly, renal defects, and a range of other developmental abnormalities. Because of their extensive phenotypic overlap, the mouse blebbing mutants have been considered models of this disorder, and the recent isolation of mutations in\n                    <jats:italic>Fras1<\/jats:italic>\n                    in both the\n                    <jats:italic>blebbed<\/jats:italic>\n                    mouse and human Fraser patients confirms this hypothesis. Here we report the identification of mutations in an extracellular matrix gene\n                    <jats:italic>Fras1-related extracellular matrix gene 1<\/jats:italic>\n                    (\n                    <jats:italic>Frem1<\/jats:italic>\n                    ) in both the classic\n                    <jats:italic>head blebs<\/jats:italic>\n                    mutant and in an\n                    <jats:italic>N<\/jats:italic>\n                    -ethyl-\n                    <jats:italic>N<\/jats:italic>\n                    -nitrosourea-induced allele. We show that inactivation of the gene results in the formation of\n                    <jats:italic>in utero<\/jats:italic>\n                    epidermal blisters beneath the lamina densa of the basement membrane and also in renal agenesis.\n                    <jats:italic>Frem1<\/jats:italic>\n                    is expressed widely in the developing embryo in regions of epithelial\/mesenchymal interaction and epidermal remodeling. Furthermore,\n                    <jats:italic>Frem1<\/jats:italic>\n                    appears to act as a dermal mediator of basement membrane adhesion, apparently independently of the other known \u201cblebs\u201d proteins Fras1 and Grip1. Unlike both\n                    <jats:italic>Fras1<\/jats:italic>\n                    and\n                    <jats:italic>Grip1<\/jats:italic>\n                    mutants, collagen VI and Fras1 deposition in the basement membrane is normal, indicating that the protein plays an independent role in epidermal differentiation and is required for epidermal adhesion during embryonic development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0402760101","type":"journal-article","created":{"date-parts":[[2004,9,2]],"date-time":"2004-09-02T20:23:54Z","timestamp":1094156634000},"page":"13560-13565","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":116,"title":["The extracellular matrix gene\n                    <i>Frem1<\/i>\n                    is essential for the normal adhesion of the embryonic epidermis"],"prefix":"10.1073","volume":"101","author":[{"given":"Ian","family":"Smyth","sequence":"first","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Du","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica J.","family":"Justice","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Beutler","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian J.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, United Kingdom; Department of Immunology, The Scripps Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom; and Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2004,9,2]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.9.623"},{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1111\/j.1399-0004.1990.tb03539.x","volume":"37","year":"1990","unstructured":"Winter, R. 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