The Role of COL1A1 and COL1A2 Mutations in Craniofacial and Dental Abnormalities in Osteogenesis Imperfecta: A Systematic Review Volume 60- Issue 3

Hafsa Shah¹* and Khuder Sadik²

• ¹Department of Population Health, University of Toledo, United States
• ²Department of Medicine, Statistics and Public Health, University of Toledo, United States

Received: January 21, 2025; Published: January 28, 2025

*Corresponding author: Dr. Hafsa Shah, BDS, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

DOI: 10.26717/BJSTR.2025.60.009445

Abstract PDF

Osteogenesis imperfecta (OI), a genetic disorder characterized by brittle bones, often results in craniofacial and dental abnormalities due to mutations in the COL1A1 and COL1A2 genes. This systematic review aimed to evaluate the relationship between these mutations and craniofacial and dental phenotypes in OI patients. Using the PRISMA guidelines, 12 studies meeting inclusion criteria were analyzed and findings revealed that structural mutations, particularly glycine substitutions in COL1A2, were strongly associated with dentinogenesis imperfecta (DI), with a prevalence of 67.6%, compared to 45.4% in COL1A1 mutations. Craniofacial anomalies, including Class II malocclusion and mandibular hypoplasia, were commonly linked to COL1A1 mutations. This review emphasizes the importance of genotype-specific assessments in predicting craniofacial and dental outcomes in OI patients. The findings support the need for personalized dental and orthodontic care and pave the way for targeted genetic and therapeutic research.

Keywords: Osteogenesis Imperfecta; COL1A1; COL1A2

Osteogenesis imperfecta (OI), or brittle bone disease, is a rare genetic disorder characterized by fragile bones, low bone density, and craniofacial and dental abnormalities (Marçal, et al. [1]. Its prevalence is approximately 1 in 15,000-20,000 live births (Mahneva, et al. [2]). OI is classified into Sillence types I–IV: Type I is mild, featuring childhood fractures, blue sclera, and occasional dentinogenesis imperfecta (DI). Type II is perinatal lethal, while Type III is the most severe form compatible with survival, involving frequent fractures and severe deformities. Type IV is moderately deforming with variable phenotypes (Mei, et al. [3]). A fifth type, OI Type V, is distinct in lacking DI and presenting unique craniofacial and dental features (Retrouvey, et al. [4]). Approximately 85–90% of OI cases are caused by autosomal dominant mutations in the COL1A1 and COL1A2 genes, which encode the α1(I) and α2(I) chains of type I collagen, a key structural protein critical for skeletal integrity (Mahneva, et al. [2]). Type I collagen constitutes 85% of the skeletal organic matrix, providing tensile strength through its characteristic Gly-X-Y triplet structure (Lindahl, et al. [5]). Glycine’s small size is crucial for collagen triple-helix stability; its substitution by larger or charged amino acids disrupts this structure, causing skeletal deformities, blue sclera, and dentinogenesis imperfecta (DI) (Andersson, et al. [2,6]). Figures 1 & 2 show DI frequency and mutation locations (Included after references) [7]. Craniofacial abnormalities, including mandibular hypoplasia, midface deficiency, and malocclusion, significantly affect oral health and quality of life in OI patients (Lindahl, et al. [5]).

Figure 1

Figure 2

DI, characterized by fragile and discolored teeth, is more prevalent in severe OI types (III and IV) and strongly associated with C-terminal mutations in collagen (Paduano, et al. [5,8]). Phenotypic variability in OI is influenced by the type and location of mutations within COL1A1 and COL1A2. Glycine substitutions account for 74.8% and 89.6% of DI-related mutations in COL1A1 and COL1A2, respectively, highlighting their role in pathological dentinogenesis (Yamaguti, et al. [7]). While these genetic alterations have been studied, detailed analyses linking specific mutations to craniofacial and dental outcomes remain limited. Understanding genotype-phenotype relationships is critical for guiding personalized dental and orthodontic care and developing targeted therapies. This study aims to systematically review the existing evidence on COL1A1 and COL1A2 mutations and their impact on craniofacial and dental phenotypes in OI, identifying knowledge gaps and future research priorities.

A systematic review of the literature was conducted using the PubMed Advanced Database. The key terms used in the search included: “Osteogenesis Imperfecta,” “genetic mutations,” “craniofacial abnormalities,” and “dental abnormalities.” The search was limited to studies published in English from 2010 to the present. Articles that focused on the relationship between COL1A1 or COL1A2 mutations and craniofacial or dental abnormalities in OI patients were considered for inclusion. The selection process followed the PRISMA guidelines, with a flow diagram created to illustrate the identification, screening, and inclusion of relevant studies. Data extracted from the studies included author information, year of publication, sample size, mutation types, and reported craniofacial and dental abnormalities. Figure 3- Prisma flow diagram (included after references). The findings were synthesized narratively, as the included studies varied in design, population, and reported outcomes. Data was organized by outcome type (e.g., dentinogenesis imperfecta, malocclusion) and by mutation (COL1A1 or COL1A2). Studies were compared qualitatively to identify common findings, trends, and discrepancies in the reported associations between mutations and phenotypic outcomes.

Figure 3

Study Selection and Data Extraction

Studies were Included if they:

1. Reported data on craniofacial and/or dental abnormalities in OI patients.
2. Provided information on COL1A1 or COL1A2 mutations.
3. Were original research articles, including case-control studies, cohort studies, or case reports.

Studies were Excluded if they:

1. Did not report craniofacial or dental outcomes.
2. Did not report information on genetic mutations
3. Focused on non-human subjects.
4. Did not have full-text access available.

Description of Studies Included in the Analysis

A total of 12 studies were included in this review, published between 2010 to present. These studies primarily focused on the relationship between COL1A1 and COL1A2 mutations and craniofacial and dental abnormalities in individuals with osteogenesis imperfecta (OI). Study designs included retrospective cohort studies, case-control studies, observational analyses, and experimental genetic studies, with sample sizes ranging from single case reports to cohorts of 223 participants. The key outcomes assessed across the studies were dentinogenesis imperfecta (DI), malocclusion, hypodontia, and other craniofacial anomalies, such as mandibular hypoplasia and midface deficiency. A common finding was that COL1A2 mutations were more strongly associated with dentinogenesis imperfecta, whereas COL1A1 mutations were linked to a broader range of craniofacial abnormalities (Table 1) [9-12].

Table 1: Description of Studies.

Findings Across Studies

The studies consistently reported that COL1A2 mutations were more frequently linked to dentinogenesis imperfecta (DI) than COL1A1 mutations (Andersson, et al. [1,6,7]) found that DI was present in 67.6% of individuals with COL1A2 mutations, compared to 45.4% in those with COL1A1 mutations. with qualitative mutations, particularly missense variants, being strongly associated with DI occurrence (p < 0.0001). COL1A1 mutations, particularly those involving glycine substitutions near p.Gly305, were strongly associated with DI in both primary and permanent dentitions (Andersson, et al. [6]).Craniofacial abnormalities, such as malocclusion and mandibular hypoplasia, were also more commonly associated with COL1A1 mutations ( Augusciak- Duma, et al. [5, 10]). Hypodontia and tooth impaction were linked to both COL1A1 and COL1A2 mutations (Marçal, et al. [1]). Overall, the studies reviewed show consistent evidence linking COL1A1 and COL1A2 mutations to significant craniofacial and dental abnormalities in OI patients. COL1A2 mutations were more strongly associated with dentinogenesis imperfecta, while COL1A1 mutations were linked to a broader range of craniofacial abnormalities. Some studies also investigated novel mutations and their implications for the OI phenotype (Li, et al. [8,12]). These findings emphasize the importance of genetic testing in diagnosis, phenotypic classification, and personalized management of OI-related anomalies.

This systematic review highlights the significant association between COL1A1 and COL1A2 mutations and the development of craniofacial and dental abnormalities in osteogenesis imperfecta (OI). Over 85% of OI cases are linked to mutations in these genes, which encode procollagen type I. Mutations affecting the triple helix domain, particularly missense mutations, impair collagen incorporation into procollagen, contributing to severe phenotypes like OI Type III (Augusciak-Duma, et al. [10]).Both COL1A1 and COL1A2 mutations lead to structural or quantitative defects in type I collagen, a critical component in tooth development. During the late bell stage, type I collagen plays an essential role in facilitating predentin secretion (Andersson, et al. [9]). These mutations are significant contributors to dentinogenesis imperfecta (DI), observed in approximately 75% of moderate-to-severe OI cases (Marçal, et al. [1,8]). Notably, COL1A2 glycine substitutions are strongly linked to DI, characterized by brittle and discolored teeth (Yamaguti, et al. [7]). In contrast, COL1A1 mutations are implicated in a broader spectrum of craniofacial abnormalities, including malocclusion, mandibular hypoplasia, and midface deficiency (Lindahl, et al. [5,10]). Notably, glycine substitutions near p.Gly305 in COL1A1 result in DI in both dentitions, affecting 70% of individuals. These mutations are also associated with permanent molar retention and taurodontism, underscoring the role of type I collagen in tooth morphogenesis (Andersson, et al. [9]). Shared features, such as hypodontia and tooth impaction, further illustrate the complex genotype-phenotype relationships in OI (Marçal, et al. [1]).

The findings emphasize the importance of genetic testing in predicting and managing craniofacial and dental abnormalities. For instance, COL1A2 mutations necessitate vigilant monitoring for DI, while craniofacial anomalies benefit from a multidisciplinary approach involving geneticists, dentists, and orthopedic specialists. Additionally, bisphosphonate therapy requires careful monitoring to mitigate potential delays in tooth eruption and developmental anomalies (Marçal, et al. [1]). Emerging research on patient-specific induced pluripotent stem cells (iPSCs) offers promise for understanding the mechanisms of OI and developing targeted therapies. Li, et al. [12] demonstrated the utility of iPSCs in preserving donor-specific genetic traits, enabling the exploration of biochemical pathways and the development of targeted treatments. Novel mutations, such as COL1A1 (p.G242V), continue to expand the genetic spectrum of DI and OI, identifying new therapeutic targets (Li, et al. [8,12]). Despite these advances, several limitations persist. Small sample sizes and inconsistent diagnostic criteria for craniofacial and dental abnormalities hinder the generalizability of findings and complicate cross-study comparisons. Retrospective studies often introduce biases and incomplete phenotype documentation, further limiting conclusions. Future research should prioritize larger, multicenter studies to address these gaps. Standardizing diagnostic criteria and elucidating molecular mechanisms underlying OI’s phenotypic diversity are critical for refining diagnostic and therapeutic strategies.

This systematic review was done to understand the significant association between COL1A1 and COL1A2 mutations and craniofacial and dental abnormalities in osteogenesis imperfecta (OI). COL1A2 mutations, particularly glycine substitutions, were strongly linked to dentinogenesis imperfecta, while COL1A1 mutations were associated with a broader spectrum of craniofacial defects such as malocclusion and mandibular hypoplasia. These findings highlight the importance of genetic testing for guiding personalized treatment plans, including early dental interventions and orthodontic care. Future research should focus on large-scale, longitudinal studies to further explore genotype-phenotype correlations and improve the clinical management of OI-related abnormalities.

The authors declared no conflict of interest.

None.

All authors drafted the manuscript, critically revised the manuscript and reviewed the literature. All authors read and approved the final manuscript.

1. All authors have participated in the work and have reviewed and agree with the content of the article.
2. None of the article contents are under consideration for publication in any other journal or have been published in any journal.
3. No portion of the text has been copied from other material in the literature (unless in quotation marks, with citation).
4. I am aware that it is the authors responsibility to obtain permission for any figures or tables reproduced from any prior publications, and to cover fully any costs involved. Such permission must be obtained prior to final acceptance.

The authors declare that all the data supporting the findings of this study are available within the manuscript.

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