{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T19:40:03Z","timestamp":1790278803265,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Despite increasing evidence that common genetic variation contributes to variation in jaw and cranial base morphology, the biological mechanisms underlying malocclusion remain poorly defined. This study tested the hypothesis that a noncoding variant near\n                      <jats:italic>TWIST1<\/jats:italic>\n                      alters craniofacial development by disrupting transcriptional regulation, contributing to skeletal phenotypes associated with malocclusion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In a cohort of 277 non-syndromic individuals with malocclusion, we performed targeted genotyping and deep sequencing of the\n                      <jats:italic>TWIST1<\/jats:italic>\n                      locus, followed by multivariate genotype\u2013phenotype correlation analyses. To evaluate regulatory function, we performed luciferase reporter assays and chromatin immunoprecipitation in multiple cell lines. Craniofacial consequences of\n                      <jats:italic>Twist1<\/jats:italic>\n                      loss of function were characterized using 3D morphometrics and craniometric analysis in conditional knockout mice at postnatal days 14 and 21.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The SNP rs2189000, located 4.2 kb upstream of\n                      <jats:italic>TWIST1<\/jats:italic>\n                      , showed a significant association with mandibular and anterior cranial base shape (P = 0.0003). No coding mutations were detected. Functional assays revealed that rs2189000 disrupts a conserved\n                      <jats:italic>PITX2<\/jats:italic>\n                      binding site, abolishing\n                      <jats:italic>PITX2<\/jats:italic>\n                      -mediated activation of\n                      <jats:italic>TWIST1<\/jats:italic>\n                      transcription. In mice, mesoderm-specific deletion of\n                      <jats:italic>Twist1<\/jats:italic>\n                      produced craniofacial changes, such as domed skulls, mandibular shortening, palatal rotation, and facial asymmetry, that paralleled the human phenotypic associations. Additionally, premature closure of the cranial base synchondroses was observed, indicating a mechanistic link to disrupted postnatal growth trajectories.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study identifies a putative functional noncoding variant that dysregulates\n                      <jats:italic>TWIST1<\/jats:italic>\n                      via disruption of\n                      <jats:italic>PITX2<\/jats:italic>\n                      DNA binding and links this effect to postnatal craniofacial phenotypes in both humans and mice. These findings expand the developmental and genetic framework for understanding malocclusion and suggest a broader role for\n                      <jats:italic>TWIST1<\/jats:italic>\n                      in cranial base growth and midface patterning.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1749243","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T22:10:11Z","timestamp":1771279811000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the role of TWIST1 in malocclusion and craniofacial morphology"],"prefix":"10.3389","volume":"17","author":[{"given":"Clarissa S. G.","family":"Da Fontoura","sequence":"first","affiliation":[{"name":"Department of Restorative Sciences, Cariology and Endodontics, School of Dentistry, University of Michigan","place":["Ann Arbor, MI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Eliason","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad A.","family":"Amendt","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa","place":["Iowa City, IA, United States"]},{"name":"Iowa Institute for Oral Health Research, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]},{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline L.","family":"Petrin","sequence":"additional","affiliation":[{"name":"Iowa Institute for Oral Health Research, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]},{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M.","family":"Moreno Uribe","sequence":"additional","affiliation":[{"name":"Iowa Institute for Oral Health Research, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]},{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa","place":["Iowa City, IA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1177\/10556656221090844","article-title":"Postnatal progressive craniosynostosis in syndromic conditions: two patients with saethre-chotzen due to TWIST1 gene deletions and review of the literature","volume":"60","author":"Alawneh","year":"2023","journal-title":"Cleft Palate Craniofac J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.3389\/fphys.2011.00037","article-title":"Craniosynostosis of coronal suture in Twist1+\/\u2212 mice occurs through endochondral ossification recapitulating the physiological closure of posterior frontal suture","volume":"2","author":"Behr","year":"2011","journal-title":"Front. 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