{ "abstract": "Primary cilia play an essential role in molecular signaling transduction during development, coordinating cell fate decisions and morphogenesis. Defects in components of the primary cilium result in an array of developmental syndromes called ciliopathies. Here we report 24 patients with nine rare and seven novel variants in the primary cilia gene C2CD3, which has previously been implicated in the ciliopathy Orofaciodigital syndrome XIV. Patients displayed an array of dental defects impacting the number, shape, and timing of tooth development. To understand the etiology underlying these defects, murine and avian models were analyzed during embryonic development. Ap2Cre;C2cd3ex4-5 fl/fl mouse mutants showed a range of dental defects prenatally, mimicking several of the phenotypes observed in patients. Shh was upregulated in the developing upper jaw, leading to a widening of the midline, while Shh expression in the lower jaw was reduced, highlighting the context-dependent impact of cilia on hedgehog signaling. In avian mutants carrying a C2CD3 variant, talpid2, tooth buds were evident with SHH expression upregulated during early development in both upper and lower jaws. Cartilage defects were additionally observed in both conditional mouse knockouts and talpid2 embryos. These changes in Shh signaling provide a mechanism to explain the phenotypes in patients and highlight the conserved role of C2CD3 in coordinating the morphogenetic potential of the jaw and patterning of the forming dentition. Given the conserved phenotypes, alterations in C2CD3-dependent ciliogenesis may have played a role in modulating Shh signaling to alter the timing and position of tooth germs across vertebrate evolution.", "abstract_shown": true, "affiliations": [ "Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand", "Division of Pediatric Dentistry, Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand", "Department of Pedodontics, Faculty of Dentistry, Istanbul University, Istanbul 34116, Türkiye", "Dental department, Rayong Hospital, Rayong 21000, Thailand", "Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229", "Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267", "Division of Plastic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229", "Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, United Kingdom", "Faculty of Dentistry, Burapha University, Saen Suk, Chon Buri 20131, Thailand", "Dental section, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkoknoi, Bangkok 10700, Thailand", "Medical Molecular Biotechnology Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand", "Dental Department, Samitivej Sukhumvit Hospital, Bangkok 10110, Thailand", "Division of Orthodontics, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand", "Fun Dee Clinic, Bangkok 10900, Thailand", "Orthodontic Section, Department of Preventive Dentistry, Faculty of Dentistry, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand", "Biomedical Sciences Division, King Abdullah University of Science and Technology Center of Excellence for Smart Health, King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia", "Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Türkiye", "Division of Oral Anatomy, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan" ], "article_type": "research article", "arxiv": null, "author_total": 21, "authors": [ { "affs": [ 0, 1 ], "name": "Piranit Kantaputra", "orcid": "0000-0001-9841-0881" }, { "affs": [ 2 ], "name": "Yeliz Guven", "orcid": "0000-0002-4637-6025" }, { "affs": [ 3 ], "name": "Narumon Bunpiem" }, { "affs": [ 4, 5, 6 ], "name": "Kimberly Cochran", "orcid": "0009-0001-4411-0653" }, { "affs": [ 7 ], "name": "Tengyang Qiu" }, { "affs": [ 4, 5, 6 ], "name": "Evan C. Brooks", "orcid": "0000-0003-4895-8296" }, { "affs": [ 8 ], "name": "Paisan Kangvonkit" }, { "affs": [ 9 ], "name": "Saisupee Arayasantiwong" }, { "affs": [ 10 ], "name": "Chumpol Ngamphiw", "orcid": "0000-0002-8581-397X" }, { "affs": [ 10 ], "name": "Sissades Tongsima" }, { "affs": [ 11 ], "name": "Puckpring Sompoprungroat" }, { "affs": [ 1 ], "name": "Nuttaporn Sengtae" }, { "affs": [ 12 ], "name": "Kanoknart Chintakanon" }, { "affs": [ 13 ], "name": "Saisinee Ngaohiranpat" }, { "affs": [ 14 ], "name": "Chidchanok Leetanakul", "orcid": "0000-0002-4450-3393" }, { "affs": [ 15 ], "name": "Stefan T. Arold", "orcid": "0000-0001-5278-0668" }, { "affs": [ 16 ], "name": "Tügba Kalayci" }, { "affs": [ 17 ], "name": "Katsushige Kawasaki", "orcid": "0009-0000-1816-1337" }, { "affs": [ 17 ], "name": "Atsushi Ohazama", "orcid": "0000-0002-3496-0347" }, { "affs": [ 4, 5, 6 ], "name": "Samantha A. Brugmann", "orcid": "0000-0002-6860-6450" }, { "affs": [ 7 ], "name": "Abigail S. Tucker", "orcid": "0000-0001-8871-6094" } ], "bibtex": "https://research.draconitic.com/paper/4r5med53j618y.bib", "cited_by": 0, "doi": "10.1073/pnas.2603057123", "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13732202/", "id": "4r5med53j618y", "issns": [ "0027-8424", "1091-6490" ], "landing_url": "https://doi.org/10.1073/pnas.2603057123", "language": "en", "licence": "CC-BY-NC-ND-4.0", "licence_label": "CC BY-NC-ND 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "412" ], [ "heading", "Biological Sciences" ], [ "heading", "Developmental Biology" ], [ "openalex", "3500|dental development and anomalies" ] ], "openalex": "W7224085369", "pdf_url": "https://www.pnas.org/doi/pdf/10.1073/pnas.2603057123", "pmcid": "PMC13732202", "pmid": "42949964", "published": "2026-10-28", "publisher": "National Academy of Sciences", "ris": "https://research.draconitic.com/paper/4r5med53j618y.ris", "sources": [ { "first_seen": "2026-11-08T12:22:13Z", "native_id": "PMC13732202", "source": "pmc", "url": "https://doi.org/10.1073/pnas.2603057123" } ], "subjects": [ { "field": "biology", "origin": "heading:Developmental Biology", "subfield": "developmental-biology" } ], "title": "C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates", "title_text": "C2CD3 links tooth patterning to evolutionary tooth loss in birds and dental anomalies across vertebrates", "type": "peer-reviewed", "updated_at": "2026-11-08T12:22:13Z", "url": "https://research.draconitic.com/paper/4r5med53j618y", "venue": "Proceedings of the National Academy of Sciences of the United States of America", "versions": [] }