{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:11:40Z","timestamp":1769163100796,"version":"3.49.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T00:00:00Z","timestamp":1626998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE026172"],"award-info":[{"award-number":["DE026172"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["F31DE027284"],"award-info":[{"award-number":["F31DE027284"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM102801"],"award-info":[{"award-number":["GM102801"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center of Biomedical Research Excellence","award":["P20 GM104936"],"award-info":[{"award-number":["P20 GM104936"]}]},{"name":"Kansas IDeA Network for Biomedical Research Excellence","award":["P20 GM103418"],"award-info":[{"award-number":["P20 GM103418"]}]},{"name":"Kansas Intellectual and Developmental Disabilities Research Center","award":["HD090216"],"award-info":[{"award-number":["HD090216"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1S10OD023625"],"award-info":[{"award-number":["1S10OD023625"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Patients with autosomal dominant SPECC1L variants show syndromic malformations, including hypertelorism, cleft palate and omphalocele. These SPECC1L variants largely cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1l\u0394Ex4) lacking the entire SPECC1L protein. Homozygous mutants for these truncations died perinatally without cleft palate or omphalocele. Given the clustering of human variants in CCD2, we hypothesized that targeted perturbation of CCD2 may be required. Indeed, homozygotes for in-frame deletions involving CCD2 (Specc1l\u0394CCD2) resulted in exencephaly, cleft palate and ventral body wall closure defects (omphalocele). Interestingly, exencephaly and cleft palate were never observed in the same embryo. Further examination revealed a narrower oral cavity in exencephalic embryos, which allowed palatal shelves to elevate and fuse despite their defect. In the cell, wild-type SPECC1L was evenly distributed throughout the cytoplasm and colocalized with both microtubules and filamentous actin. In contrast, mutant SPECC1L-\u0394CCD2 protein showed abnormal perinuclear accumulation with diminished overlap with microtubules, indicating that SPECC1L used microtubule association for trafficking in the cell. The perinuclear accumulation in the mutant also resulted in abnormally increased actin and non-muscle myosin II bundles dislocated to the cell periphery. Disrupted actomyosin cytoskeletal organization in SPECC1L CCD2 mutants would affect cell alignment and coordinated movement during neural tube, palate and ventral body wall closure. Thus, we show that perturbation of CCD2 in the context of full SPECC1L protein affects tissue fusion dynamics, indicating that human SPECC1L CCD2 variants are gain-of-function.<\/jats:p>","DOI":"10.1093\/hmg\/ddab211","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T19:32:58Z","timestamp":1626809578000},"page":"18-31","source":"Crossref","is-referenced-by-count":15,"title":["In-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events"],"prefix":"10.1093","volume":"31","author":[{"given":"Jeremy P","family":"Goering","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke W","family":"Wenger","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Stetsiv","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Moedritzer","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Everett G","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dona Greta","family":"Isai","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brittany M","family":"Jack","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaid","family":"Umar","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison K","family":"Rickabaugh","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andras","family":"Czirok","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Department of Biological Physics, Eotvos University, Budapest 1053, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6250-6651","authenticated-orcid":false,"given":"Irfan","family":"Saadi","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,7,23]]},"reference":[{"key":"2021121717442091400_ref1","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0955-0674(02)00369-1","article-title":"Epithelial fusions in the embryo","volume":"14","author":"Martin","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"2021121717442091400_ref2","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1242\/dev.068338","article-title":"Mechanisms of tissue fusion during development","volume":"139","author":"Ray","year":"2012","journal-title":"Development"},{"key":"2021121717442091400_ref3","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1002\/bdr2.1589","article-title":"National population-based estimates for major birth defects, 2010-2014","volume":"111","author":"Mai","year":"2019","journal-title":"Birth Defects Res."},{"key":"2021121717442091400_ref4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ajhg.2011.05.023","article-title":"Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting","volume":"89","author":"Saadi","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2021121717442091400_ref5","doi-asserted-by":"crossref","DOI":"10.1038\/srep17735","article-title":"SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination","volume":"6","author":"Wilson","year":"2016","journal-title":"Sci. Rep."},{"key":"2021121717442091400_ref6","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/hmg\/ddaa002","article-title":"SPECC1L regulates palate development downstream of IRF6","volume":"29","author":"Hall","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"2021121717442091400_ref7","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1136\/jmedgenet-2014-102677","article-title":"Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G\/BBB syndrome","volume":"52","author":"Kruszka","year":"2015","journal-title":"J. Med. Genet."},{"key":"2021121717442091400_ref8","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1002\/ajmg.a.37217","article-title":"Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome","volume":"167A","author":"Bhoj","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"2021121717442091400_ref9","article-title":"Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes","author":"Bhoj","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"2021121717442091400_ref10","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/s41598-021-81123-9","article-title":"SPECC1L-deficient primary mouse embryonic palatal mesenchyme cells show speed and directionality defects","volume":"11","author":"Goering","year":"2021","journal-title":"Sci. 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