Journal article
Exploring the role of TWIST1 in malocclusion and craniofacial morphology
Frontiers in physiology, Vol.17, 1749243
02/01/2026
DOI: 10.3389/fphys.2026.1749243
PMCID: PMC12952720
PMID: 41778196
Abstract
ObjectiveDespite 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 TWIST1 alters craniofacial development by disrupting transcriptional regulation, contributing to skeletal phenotypes associated with malocclusion.MethodsIn a cohort of 277 non-syndromic individuals with malocclusion, we performed targeted genotyping and deep sequencing of the TWIST1 locus, followed by multivariate genotype–phenotype correlation analyses. To evaluate regulatory function, we performed luciferase reporter assays and chromatin immunoprecipitation in multiple cell lines. Craniofacial consequences of Twist1 loss of function were characterized using 3D morphometrics and craniometric analysis in conditional knockout mice at postnatal days 14 and 21.ResultsThe SNP rs2189000, located 4.2 kb upstream of TWIST1, 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 PITX2 binding site, abolishing PITX2-mediated activation of TWIST1 transcription. In mice, mesoderm-specific deletion of Twist1 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.ConclusionThis study identifies a putative functional noncoding variant that dysregulates TWIST1 via disruption of PITX2 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 TWIST1 in cranial base growth and midface patterning.
Details
- Title: Subtitle
- Exploring the role of TWIST1 in malocclusion and craniofacial morphology
- Creators
- Clarissa S. G. Da Fontoura - American Association of EndodontistsSteven Eliason - University of IowaBrad A. Amendt - University of IowaAline L. Petrin - University of IowaLina M Moreno Uribe - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Frontiers in physiology, Vol.17, 1749243
- DOI
- 10.3389/fphys.2026.1749243
- PMID
- 41778196
- PMCID
- PMC12952720
- ISSN
- 1664-042X
- eISSN
- 1664-042X
- Publisher
- Frontiers Media S.A
- Grant note
- AAOF: OFDFA_2008 National Center for Advancing Translational SciencesNational Institutes of Health (NIH): DE013941, 2 UL1 TR000442-06, T32-DEO14678-09 NIH/NIDCR: R90 T90 DE023520, R90DE024296
The author(s) declared that financial support was received for this work and/or its publication. We thank all the members of the BA laboratory for their help with the laboratory protocols. AAOF OFDFA_2008 provided this funding for AAOF project-2011 and AAOF BRA 2012. Also supported by the National Center for Advancing Translational Sciences, and the National Institutes of Health (NIH), through Grants DE013941, 2 UL1 TR000442-06 and T32-DEO14678-09, and by NIH/NIDCR Award R90 T90 DE023520, R90DE024296. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
- Language
- English
- Date published
- 02/01/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Orthodontics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985139308202771
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