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For many individuals, the genetic etiology is unknown. Through whole-exome and targeted sequencing, we detected three novel variants in a gene encoding a transcription factor, PRDM1, that arose de novo in families with SHFM or segregated with the phenotype. PRDM1 is required for limb development; however, its role is not well understood and it is unclear how the PRDM1 variants affect protein function. Using transient and stable overexpression rescue experiments in zebrafish, we show that the variants disrupt the proline\/serine-rich and DNA-binding zinc finger domains, resulting in a dominant-negative effect. Through gene expression assays, RNA sequencing, and CUT&amp;RUN in isolated pectoral fin cells, we demonstrate that Prdm1a directly binds to and regulates genes required for fin induction, outgrowth and anterior\/posterior patterning, such as fgfr1a, dlx5a, dlx6a and smo. Taken together, these results improve our understanding of the role of PRDM1 in the limb gene regulatory network and identified novel PRDM1 variants that link to SHFM in humans.<\/jats:p>","DOI":"10.1242\/dmm.049977","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T14:12:54Z","timestamp":1682086374000},"source":"Crossref","is-referenced-by-count":10,"title":["PRDM1 DNA-binding zinc finger domain is required for normal limb development and is disrupted in split hand\/foot malformation"],"prefix":"10.1242","volume":"16","author":[{"given":"Brittany T.","family":"Truong","sequence":"first","affiliation":[{"name":"University of Colorado Denver Anschutz Medical Campus 1 Human Medical Genetics & Genomics Graduate Program , , Aurora, CO 80045 , USA"},{"name":"University of Colorado Denver Anschutz Medical Campus 2 Department of Craniofacial Biology , , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lomeli C.","family":"Shull","sequence":"additional","affiliation":[{"name":"University of Colorado Denver Anschutz Medical Campus 2 Department of Craniofacial Biology , , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6795-0260","authenticated-orcid":false,"given":"Ezra","family":"Lencer","sequence":"additional","affiliation":[{"name":"Lafayette College 3 Biology Department , , Easton, PA 18042 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"Bend","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center 4 , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Field","sequence":"additional","affiliation":[{"name":"Genetics of Learning Disability Service, Hunter Genetics 5 , Waratah, NSW 2298 , AUS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth E.","family":"Blue","sequence":"additional","affiliation":[{"name":"University of Washington 6 Division of Medical Genetics, Department of Medicine , , Seattle, WA 98195 , USA"},{"name":"Brotman-Baty Institute for Precision Medicine 7 , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Brotman-Baty Institute for Precision Medicine 7 , Seattle, WA 98195 , USA"},{"name":"University of Washington 8 Division of Genetic Medicine, Department of Pediatrics , , Seattle, WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Skinner","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center 4 , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Everman","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center 4 , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center 4 , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Flanagan-Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetics Center 4 , Greenwood, SC 29646 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3003-6042","authenticated-orcid":false,"given":"Kristin B.","family":"Artinger","sequence":"additional","affiliation":[{"name":"University of Colorado Denver Anschutz Medical Campus 2 Department of Craniofacial Biology , , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"2023052213234066700_DMM049977C1","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1242\/dev.00191","article-title":"Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo","volume":"130","author":"Agarwal","year":"2003","journal-title":"Development"},{"key":"2023052213234066700_DMM049977C2","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.ydbio.2008.06.032","article-title":"Tri-phasic expression of posterior Hox genes during development of pectoral fins in zebrafish: implications for the evolution of vertebrate paired appendages","volume":"322","author":"Ahn","year":"2008","journal-title":"Dev. 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