{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T21:56:19Z","timestamp":1772142979930,"version":"3.50.1"},"reference-count":27,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2006,2,6]],"date-time":"2006-02-06T00:00:00Z","timestamp":1139184000000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2006,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Cleidocranial dysplasia (CCD) is an autosomal\u2010dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor<jats:italic>RUNX2<\/jats:italic>, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype\u2010phenotype correlation has emerged.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C\u2010terminal region of<jats:italic>RUNX2<\/jats:italic>distal to the DNA\u2010binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C\u2010terminal mutations that preserve the runt domain may lead to more\u2010severe craniofacial phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Upon mutational analysis of<jats:italic>RUNX2<\/jats:italic>, we identified either frameshift or splice\u2010site mutations that affect the C\u2010terminal region of the resultant protein distal to the runt domain.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>In the context of previously described mutations, these cases suggest that C\u2010terminal mutations that preserve the DNA\u2010binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.<jats:italic>Birth Defects Research (Part A)<\/jats:italic>Birth Defects Research (Part A), 2006. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.20231","type":"journal-article","created":{"date-parts":[[2006,2,7]],"date-time":"2006-02-07T00:16:55Z","timestamp":1139271415000},"page":"78-85","source":"Crossref","is-referenced-by-count":38,"title":["Cleidocranial dysplasia with severe parietal bone dysplasia: C\u2010terminal<i>RUNX2<\/i>mutations"],"prefix":"10.1002","volume":"76","author":[{"given":"Michael L.","family":"Cunningham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne L.","family":"Seto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne V.","family":"Hing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilyn J.","family":"Bull","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Hopkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen A.","family":"Leppig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,2,6]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012758925617"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.151236498"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0177(2000)9999:9999<::AID-DVDY1074>3.0.CO;2-C"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(200009)16:3<277::AID-HUMU25>3.0.CO;2-V"},{"issue":"3","key":"e_1_2_6_6_1","first-page":"113","article-title":"A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplaia (CCD) and variable expressivity","volume":"20","author":"Golan I","year":"2000","journal-title":"J Craniofac Genet Dev Biol."},{"key":"e_1_2_6_7_1","first-page":"249","volume-title":"Syndromes of the head and neck","author":"Gorlin R","year":"1990"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1050"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0797-307"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0004.2002.610505.x"},{"key":"e_1_2_6_11_1","first-page":"456","article-title":"Sur un deplacment natural de la clavicule","volume":"23","author":"Martin","year":"1765","journal-title":"J Med Chir Pharmacol"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80260-3"},{"key":"e_1_2_6_13_1","volume-title":"Online Mendelian Inheritance in Man. 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