{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:33:15Z","timestamp":1791325995502,"version":"4.3.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,20]],"date-time":"2016-04-20T00:00:00Z","timestamp":1461110400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,20]],"date-time":"2016-04-20T00:00:00Z","timestamp":1461110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ciliopathies are a group of genetic disorders caused by defective assembly or dysfunction of the primary cilium, a microtubule-based cellular organelle that plays a key role in developmental signalling. Ciliopathies are clinically grouped in a large number of overlapping disorders, including the orofaciodigital syndromes (OFDS), the short rib polydactyly syndromes and Jeune asphyxiating thoracic dystrophy. Recently, mutations in the gene encoding the centriolar protein C2CD3 have been described in two families with a new sub-type of OFDS (OFD14), with microcephaly and cerebral malformations. Here we describe a third family with novel compound heterozygous <jats:italic>C2CD3<\/jats:italic> mutations in two fetuses with a different clinical presentation, dominated by skeletal dysplasia with no microcephaly. Analysis of fibroblast cultures derived from one of these fetuses revealed a reduced ability to form cilia, consistent with previous studies in <jats:italic>C2cd3<\/jats:italic>-mutant mouse and chicken cells. More detailed analyses support a role for C2CD3 in basal body maturation; but in contrast to previous mouse studies the normal recruitment of the distal appendage protein CEP164 suggests that this protein is not sufficient for efficient basal body maturation and subsequent axonemal extension in a C2CD3-defective background.<\/jats:p>","DOI":"10.1038\/srep24083","type":"journal-article","created":{"date-parts":[[2016,4,20]],"date-time":"2016-04-20T08:55:24Z","timestamp":1461142524000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function"],"prefix":"10.1038","volume":"6","author":[{"given":"Claudio R.","family":"Cort\u00e9s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aideen M.","family":"McInerney-Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Vogel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Rond\u00f3n Galeano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica E.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa K.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Keith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette","family":"Ramsing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma L.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zankl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Wicking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,20]]},"reference":[{"key":"BFsrep24083_CR1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature12833","volume":"504","author":"M Delling","year":"2013","unstructured":"Delling, M., DeCaen, P. G., Doerner, J. F., Febvay, S. & Clapham, D. E. Primary cilia are specialized calcium signalling organelles. Nature 504, 311\u2013314 (2013).","journal-title":"Nature"},{"key":"BFsrep24083_CR2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nature02061","volume":"426","author":"D Huangfu","year":"2003","unstructured":"Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83\u201387 (2003).","journal-title":"Nature"},{"key":"BFsrep24083_CR3","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/ng.2007.54","volume":"40","author":"C Jones","year":"2008","unstructured":"Jones, C. et al. Ciliary proteins link basal body polarization to planar cell polarity regulation. Nat. Genet. 40, 69\u201377 (2008).","journal-title":"Nat. Genet."},{"key":"BFsrep24083_CR4","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/ncb2259","volume":"13","author":"MA Lancaster","year":"2011","unstructured":"Lancaster, M. A., Schroth, J. & Gleeson, J. G. Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat. Cell Biol. 13, 700\u2013707 (2011).","journal-title":"Nat. Cell Biol."},{"key":"BFsrep24083_CR5","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1083\/jcb.201110049","volume":"197","author":"KF Liem","year":"2012","unstructured":"Liem, K. F. et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J. Cell Biol. 197, 789\u2013800 (2012).","journal-title":"J. Cell Biol."},{"key":"BFsrep24083_CR6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1083\/jcb.201101005","volume":"193","author":"T Kobayashi","year":"2011","unstructured":"Kobayashi, T. & Dynlacht, B. D. Regulating the transition from centriole to basal body. J. Cell Biol. 193, 435\u2013444 (2011).","journal-title":"J. Cell Biol."},{"key":"BFsrep24083_CR7","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.cell.2007.06.027","volume":"130","author":"A Spektor","year":"2007","unstructured":"Spektor, A., Tsang, W. Y., Khoo, D. & Dynlacht, B. D. Cep97 and CP110 suppress a cilia assembly program. Cell 130, 678\u2013690, 10.1016\/j.cell.2007.06.027 (2007).","journal-title":"Cell"},{"key":"BFsrep24083_CR8","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/ncb3109","volume":"17","author":"Q Lu","year":"2015","unstructured":"Lu, Q. et al. Early steps in primary cilium assembly require EHD1\/EHD3-dependent ciliary vesicle formation. Nat. Cell Biol. 17, 228\u2013240 (2015).","journal-title":"Nat. Cell Biol."},{"key":"BFsrep24083_CR9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0070-2153(08)00802-8","volume":"85","author":"LB Pedersen","year":"2008","unstructured":"Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23\u201361 (2008).","journal-title":"Curr. Top. Dev. Biol."},{"key":"BFsrep24083_CR10","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1056\/NEJMra1010172","volume":"364","author":"F Hildebrandt","year":"2011","unstructured":"Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364, 1533\u201348 (2011).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep24083_CR11","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1002\/ajmg.a.32799","volume":"149a","author":"HV Toriello","year":"2009","unstructured":"Toriello, H. V. Are the oral-facial-digital syndromes ciliopathies? Am. J. Med. Genet. A 149a, 1089\u20131095 (2009).","journal-title":"Am. J. Med. Genet. A"},{"key":"BFsrep24083_CR12","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1136\/jmg.23.2.116","volume":"23","author":"M Baraitser","year":"1986","unstructured":"Baraitser, M. The orofaciodigital (OFD) syndromes. J. Med. Genet. 23, 116\u2013119 (1986).","journal-title":"J. Med. Genet."},{"key":"BFsrep24083_CR13","first-page":"46","volume":"3","author":"M Schmidts","year":"2014","unstructured":"Schmidts, M. Clinical genetics and pathobiology of ciliary chondrodysplasias. J. Pediatr. Genet. 3, 46\u201394 (2014).","journal-title":"J. Pediatr. Genet."},{"key":"BFsrep24083_CR14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1136\/jmg.2004.027672","volume":"43","author":"C Thauvin-Robinet","year":"2006","unstructured":"Thauvin-Robinet, C. et al. Clinical, molecular and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J. Med. Genet. 43, 54\u201361 (2006).","journal-title":"J. Med. Genet."},{"key":"BFsrep24083_CR15","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1083\/jcb.201411087","volume":"209","author":"EC Roberson","year":"2015","unstructured":"Roberson, E. C. et al. TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone. J. Cell Biol. 209, 129\u2013142 (2015).","journal-title":"J. Cell Biol."},{"key":"BFsrep24083_CR16","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.ajhg.2012.06.017","volume":"91","author":"S Thomas","year":"2012","unstructured":"Thomas, S. et al. TCTN3 mutations cause Mohr-Majewski syndrome. Am. J. Hum. Genet. 91, 372\u20138 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep24083_CR17","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.ajhg.2013.07.012","volume":"93","author":"HE Shamseldin","year":"2013","unstructured":"Shamseldin, H. E. et al. Mutations in DDX59 implicate RNA helicase in the pathogenesis of orofaciodigital syndrome. Am. J. Hum. Genet. 93, 555\u2013560 (2013).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep24083_CR18","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00439-013-1385-1","volume":"133","author":"E Lopez","year":"2014","unstructured":"Lopez, E. et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum. Genet. 133, 367\u2013377 (2014).","journal-title":"Hum. Genet."},{"key":"BFsrep24083_CR19","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/ng.594","volume":"42","author":"EM Valente","year":"2010","unstructured":"Valente, E. M. et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat. Genet. 42, 619\u2013625 (2010).","journal-title":"Nat. Genet."},{"key":"BFsrep24083_CR20","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/ng.3031","volume":"46","author":"C Thauvin-Robinet","year":"2014","unstructured":"Thauvin-Robinet, C. et al. The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation. Nat. Genet. 46, 905\u2013911 (2014).","journal-title":"Nat. Genet."},{"key":"BFsrep24083_CR21","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.1242\/dev.029835","volume":"135","author":"AN Hoover","year":"2008","unstructured":"Hoover, A. N. et al. C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development 135, 4049\u20134058 (2008).","journal-title":"Development"},{"key":"BFsrep24083_CR22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00018-014-1711-3","volume":"72","author":"MA Tollenaere","year":"2015","unstructured":"Tollenaere, M. A., Mailand, N. & Bekker-Jensen, S. Centriolar satellites: key mediators of centrosome functions. Cell. Mol. Life Sci. 72, 11\u201323 (2015).","journal-title":"Cell. Mol. Life Sci."},{"key":"BFsrep24083_CR23","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1073\/pnas.1318737111","volume":"111","author":"X Ye","year":"2014","unstructured":"Ye, X., Zeng, H., Ning, G., Reiter, J. F. & Liu, A. C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals. Proc. Natl. Acad. Sci. USA 111, 2164\u20132169 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep24083_CR24","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1242\/dev.105924","volume":"141","author":"CF Chang","year":"2014","unstructured":"Chang, C. F. et al. The cellular and molecular etiology of the craniofacial defects in the avian ciliopathic mutant talpid2. Development 141, 3003\u20133012 (2014).","journal-title":"Development"},{"key":"BFsrep24083_CR25","first-page":"855","volume":"8","author":"EN Schock","year":"2015","unstructured":"Schock, E. N. et al. Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of Oral-facial-digital syndrome. Dis. Model. Mech. 8, 855\u2013856 (2015).","journal-title":"Dis. Model. Mech."},{"key":"BFsrep24083_CR26","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248\u2013249 (2010).","journal-title":"Nat. Methods"},{"key":"BFsrep24083_CR27","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","volume":"4","author":"P Kumar","year":"2009","unstructured":"Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073\u20131081 (2009).","journal-title":"Nat. Protoc."},{"key":"BFsrep24083_CR28","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","volume":"11","author":"JM Schwarz","year":"2014","unstructured":"Schwarz, J. M., Cooper, D. N., Schuelke, M. & Seelow, D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat. Methods 11, 361\u2013362 (2014).","journal-title":"Nat. Methods"},{"key":"BFsrep24083_CR29","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.4161\/cc.22068","volume":"11","author":"D Zhang","year":"2012","unstructured":"Zhang, D. & Aravind, L. Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment. Cell cycle 11, 3861\u201375 (2012).","journal-title":"Cell cycle"},{"key":"BFsrep24083_CR30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.celrep.2014.05.049","volume":"8","author":"K Remans","year":"2014","unstructured":"Remans, K., Burger, M., Vetter, I. R. & Wittinghofer, A. C2 domains as protein-protein interaction modules in the ciliary transition zone. Cell Rep. 8, 1\u20139 (2014).","journal-title":"Cell Rep."},{"key":"BFsrep24083_CR31","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1242\/jcs.03366","volume":"120","author":"A Robert","year":"2007","unstructured":"Robert, A. et al. The intraflagellar transport component IFT88\/polaris is a centrosomal protein regulating G1-S transition in non-ciliated cells. J. Cell Sci. 120, 628\u2013637 (2007).","journal-title":"J. Cell Sci."},{"key":"BFsrep24083_CR32","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1101\/gad.207043.112","volume":"27","author":"BE Tanos","year":"2013","unstructured":"Tanos, B. E. et al. Centriole distal appendages promote membrane docking, leading to cilia initiation. Genes Dev. 27, 163\u2013168 (2013).","journal-title":"Genes Dev."},{"key":"BFsrep24083_CR33","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1083\/jcb.201303071","volume":"203","author":"K Tateishi","year":"2013","unstructured":"Tateishi, K. et al. Two appendages homologous between basal bodies and centrioles are formed using distinct Odf2 domains. J. Cell Biol. 203, 417\u2013425 (2013).","journal-title":"J. Cell Biol."},{"key":"BFsrep24083_CR34","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/ng.756","volume":"43","author":"EE Davis","year":"2011","unstructured":"Davis, E. E. et al. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat. Genet. 43, 189\u2013196 (2011).","journal-title":"Nat. Genet."},{"key":"BFsrep24083_CR35","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/hmg\/ddt394","volume":"23","author":"Y Zhang","year":"2014","unstructured":"Zhang, Y. et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum. Mol. Genet. 23, 40\u201351 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep24083_CR36","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1002\/wdev.199","volume":"4","author":"CR Cortes","year":"2015","unstructured":"Cortes, C. R., Metzis, V. & Wicking, C. Unmasking the ciliopathies: craniofacial defects and the primary cilium. Wiley Interdiscip. Rev. Dev. Biol. 4, 637\u2013 653 (2015).","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"BFsrep24083_CR37","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ajhg.2010.12.004","volume":"88","author":"C Thiel","year":"2011","unstructured":"Thiel, C. et al. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am. J. Hum. Genet. 88, 106\u2013114 (2011).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep24083_CR38","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1093\/hmg\/ddu555","volume":"24","author":"R Shaheen","year":"2015","unstructured":"Shaheen, R. et al. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies. Hum. Mol. Genet. 24, 1410\u20131419 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"BFsrep24083_CR39","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ajhg.2013.11.019","volume":"94","author":"K Tuz","year":"2014","unstructured":"Tuz, K. et al. Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am. J. Hum. Genet. 94, 62\u201372 (2014).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep24083_CR40","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.ajhg.2013.06.022","volume":"93","author":"AM McInerney-Leo","year":"2013","unstructured":"McInerney-Leo, A. M. et al. Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. Am. J. Hum. Genet. 93, 515\u2013523 (2013).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep24083_CR41","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature09534","volume":"467","author":"GR Abecasis","year":"2010","unstructured":"Abecasis, G. R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061\u20131073 (2010).","journal-title":"Nature"},{"key":"BFsrep24083_CR42","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1101\/gr.112326.110","volume":"21","author":"CA Albers","year":"2011","unstructured":"Albers, C. A. et al. Dindel: accurate indel calls from short-read data. Genome Res. 21, 961\u2013973 (2011).","journal-title":"Genome Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep24083","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T19:05:42Z","timestamp":1672859142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep24083"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,20]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,26]]}},"alternative-id":["BFsrep24083"],"URL":"https:\/\/doi.org\/10.1038\/srep24083","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,20]]},"assertion":[{"value":"11 September 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24083"}}