{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:06:39Z","timestamp":1785215199814,"version":"3.55.0"},"posted":{"date-parts":[[2024,10,28]]},"group-title":"Developmental Biology","reference-count":21,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"NIDCD","doi-asserted-by":"crossref","award":["R01DC020190"],"award-info":[{"award-number":["R01DC020190"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"NIDCD","doi-asserted-by":"crossref","award":["R01DC021795"],"award-info":[{"award-number":["R01DC021795"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000055","name":"NIDCD","doi-asserted-by":"crossref","award":["R01DC017166"],"award-info":[{"award-number":["R01DC017166"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Fraser syndrome is a rare autosomal recessive disorder characterized by multiple congenital malformations, including cryptophthalmos, syndactyly, and renal agenesis, which can lead to severe complications beginning at the embryonic stage. Mutations in genes encoding extracellular matrix proteins such as FRAS1, FREM1, FREM2, and the associated trafficking protein GRIP1, are implicated in Fraser syndrome. These proteins are critical for maintaining epithelial integrity during embryogenesis, with deficiencies leading to tissue detachment and blistering phenotypes in mouse models. The FREM2 protein is a single-pass membrane protein of 3169 amino acids. While\n                  <jats:italic>Frem2-<\/jats:italic>\n                  deficient mouse models encoding missense variants found in patients, or a truncated FREM2 protein product were previously reported, it has not been studied in a constitutive knockout (KO) mouse model.\n                <\/jats:p>\n                <jats:p>\n                  Here, we developed constitutive\n                  <jats:italic>Frem2-KO<\/jats:italic>\n                  mice exhibiting neonatal lethality, mainly due to bilateral renal agenesis, along with blood-filled blisters, cryptophthalmos, and syndactyly. Only one mouse survived to adulthood exhibiting unilateral renal agenesis and Fraser syndrome-like phenotypes. These findings confirm FREM2\u2019s crucial role in the development of the kidneys, skin, and eyes and provide an animal model for further studies of FREM2-related developmental disorders.\n                <\/jats:p>","DOI":"10.1101\/2024.10.28.620501","type":"posted-content","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T21:15:21Z","timestamp":1730150121000},"source":"Crossref","is-referenced-by-count":3,"title":["<i>Frem2<\/i>\n                  Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8074-0070","authenticated-orcid":false,"given":"Rubina G.","family":"Simikyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6986-0541","authenticated-orcid":false,"given":"Xinyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Strelkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MengYu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4921-6043","authenticated-orcid":false,"given":"Andreas","family":"Eckhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5526-7058","authenticated-orcid":false,"given":"Petr Y.","family":"Baranov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Richey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2076-6818","authenticated-orcid":false,"given":"Artur A.","family":"Indzhykulian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025080805550430000_2024.10.28.620501v2.1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi262"},{"key":"2025080805550430000_2024.10.28.620501v2.2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.9.623"},{"key":"2025080805550430000_2024.10.28.620501v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2010.12.016"},{"key":"2025080805550430000_2024.10.28.620501v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/ng1292"},{"key":"2025080805550430000_2024.10.28.620501v2.5","doi-asserted-by":"publisher","DOI":"10.1080\/15216540701510581"},{"key":"2025080805550430000_2024.10.28.620501v2.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601011103"},{"key":"2025080805550430000_2024.10.28.620501v2.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402760101"},{"key":"2025080805550430000_2024.10.28.620501v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/ng1549"},{"key":"2025080805550430000_2024.10.28.620501v2.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092130099"},{"key":"2025080805550430000_2024.10.28.620501v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/ng1168"},{"key":"2025080805550430000_2024.10.28.620501v2.11","first-page":"625492","article-title":"The Metabolic Reprogramming of Frem2 Mutant Mice Embryos in Cryptophthalmos Development","volume":"8","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"2025080805550430000_2024.10.28.620501v2.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505404102"},{"key":"2025080805550430000_2024.10.28.620501v2.13","doi-asserted-by":"publisher","DOI":"10.1080\/03008200802148025"},{"key":"2025080805550430000_2024.10.28.620501v2.14","doi-asserted-by":"crossref","unstructured":"Esho, T. , et al., The Fraser Complex Proteins (Frem1, Frem2, and Fras1) Can Form Anchoring Cords in the Absence of AMACO at the Dermal-Epidermal Junction of Mouse Skin. 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