{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T08:33:57Z","timestamp":1789893237837,"version":"4.0.1"},"reference-count":49,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DE027091"],"award-info":[{"award-number":["DE027091"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DE031039"],"award-info":[{"award-number":["DE031039"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007172","name":"Cincinnati Children's Hospital Medical Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007172","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cincinnati Children's Research Foundation"},{"DOI":"10.13039\/100006019","name":"Van Andel Research Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006019","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,2,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Frizzled 2 (FZD2) is a transmembrane Wnt receptor. We previously identified a pathogenic human FZD2 variant in individuals with FZD2-associated autosomal dominant Robinow syndrome. The variant encoded a protein with a premature stop and loss of 17 amino acids, including a region of the consensus dishevelled-binding sequence. To model this variant, we used zygote microinjection and i-GONAD-based CRISPR\/Cas9-mediated genome editing to generate a mouse allelic series. Embryos mosaic for humanized Fzd2W553* knock-in exhibited cleft palate and shortened limbs, consistent with patient phenotypes. We also generated two germline mouse alleles with small deletions: Fzd2D3 and Fzd2D4. Homozygotes for each allele exhibit a highly penetrant cleft palate phenotype, shortened limbs compared with wild type and perinatal lethality. Fzd2D4 craniofacial tissues indicated decreased canonical Wnt signaling. In utero treatment with IIIC3a (a DKK inhibitor) normalized the limb lengths in Fzd2D4 homozygotes. The in vivo replication represents an approach for further investigating the mechanism of FZD2 phenotypes and demonstrates the utility of CRISPR knock-in mice as a tool for investigating the pathogenicity of human genetic variants. We also present evidence for a potential therapeutic intervention.<\/jats:p>","DOI":"10.1242\/dev.201038","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T09:35:50Z","timestamp":1676453750000},"source":"Crossref","is-referenced-by-count":7,"title":["Successful therapeutic intervention in new mouse models of frizzled 2-associated congenital malformations"],"prefix":"10.1242","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7480-5459","authenticated-orcid":false,"given":"Ryan P.","family":"Liegel","sequence":"first","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2253-3919","authenticated-orcid":false,"given":"Megan N.","family":"Michalski","sequence":"additional","affiliation":[{"name":"Center for Cancer and Cell Biology, Van Andel Institute 2 , Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0891-1397","authenticated-orcid":false,"given":"Sanika","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-1568","authenticated-orcid":false,"given":"Elizabeth","family":"Bittermann","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Finnerty","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea A.","family":"Menke","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6526-9372","authenticated-orcid":false,"given":"Cassandra R.","family":"Diegel","sequence":"additional","affiliation":[{"name":"Center for Cancer and Cell Biology, Van Andel Institute 2 , Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhendong A.","family":"Zhong","sequence":"additional","affiliation":[{"name":"Center for Cancer and Cell Biology, Van Andel Institute 2 , Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart O.","family":"Williams","sequence":"additional","affiliation":[{"name":"Center for Cancer and Cell Biology, Van Andel Institute 2 , Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4512-6806","authenticated-orcid":false,"given":"Rolf W.","family":"Stottmann","sequence":"additional","affiliation":[{"name":"Cincinnati Children's Hospital Medical Center 1 Division of Human Genetics, Department of Pediatrics , , Cincinnati, OH 45215, USA"},{"name":"Cincinnati Children's Hospital Medical Center 3 Division of Developmental Biology, Department of Pediatrics , , Cincinnati, OH 45215, USA"},{"name":"Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital 4 , Columbus, OH 43205, USA"},{"name":"School of Medicine, Ohio State University 5 Department of Pediatrics , , Columbus, OH 43205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"2023021511035475700_","volume-title":"Manipulating the Mouse Embryo: A Laboratory Manual.","author":"Behringer","year":"2014"},{"key":"2023021511035475700_","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1002\/ajmg.a.38636","article-title":"Biallelic loss-of-function WNT5A mutations in an infant with severe and atypical manifestations of Robinow syndrome","volume":"176","author":"Birgmeier","year":"2018","journal-title":"Am. 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