Craniofacial features of cleidocranial dysplasia

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Abstract

Cleidocranial dysplasia (CCD) is an autosomal-dominant malformation syndrome affecting bones and teeth. The most common skeletal and dental abnormalities in affected individuals are hypoplastic/aplastic clavicles, open fontanelles, short stature, retention of primary teeth, delayed eruption of permanent teeth, supernumerary teeth, and multiple impacted teeth. Treatment of CCD requires a multidisciplinary approach that may include dental corrections, orthognathic surgery and cranioplasty along with management of any complications of CCD. Early diagnosis of this condition enables application of the treatment strategy that provides the best quality of life to such patients. Notably, Runx2 gene mutations have been identified in CCD patients. Therefore, further elucidation of the molecular mechanism of supernumerary teeth formation related to Runx2 mutations may improve understanding of dental development in CCD. The insights into CCD pathogenesis may assist in the development of new treatments for CCD.

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Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia.

A. L. Pastore, G Karsenty, Byung-Chul Lee … (1997)

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by hypoplastic or absent clavicles, large fontanelles, dental anomalies and delayed skeletal development. The phenotype is suggestive of a generalized defect in ossification and is one of the most common skeletal dysplasias not associated with disproportionate stature. To date, no genetic determinants of ossification have been identified. CCD has been mapped to chromosome 6p21, where CBFA1, a gene encoding OSF2/CBFA1, a transcriptional activator of osteoblast differentiation, has been localized. Here, we describe two de novo missense mutations, Met175Arg and Ser191Asn, in the OSF2/CBFA1 gene in two patients with CCD. These two mutations result in substitution of highly conserved amino acids in the DNA-binding domain. DNA-binding studies with the mutant polypeptides show that these amino acid substitutions abolish the DNA-binding ability of OSF2/CBFA1 to its known target sequence. Concurrent studies show that heterozygous nonsense mutations in OSF2/CBFA1 also result in CCD, while mice homozygous for the osf2/cbfa1 mull allele exhibit a more severe lethal phenotype. Thus, these results together suggest that CCD is produced by haploinsufficiency of OSF2/CBFA1 and provide direct genetic evidence that the phenotype is secondary to an alteration of osteoblast differentiation.

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Cleidocranial dysplasia: clinical and molecular genetics.

S Mundlos (1999)

Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. The disease gene has been mapped to chromosome 6p21 within a region containing CBFA1, a member of the runt family of transcription factors. Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD. The function of CBFA1 during skeletal development was further elucidated by the generation of mutated mice in which the Cbfa1 gene locus was targeted. Loss of one Cbfa1 allele (+/-) leads to a phenotype very similar to human CCD, featuring hypoplasia of the clavicles and patent fontanelles. Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation. These studies show that haploinsufficiency of CBFA1 causes the CCD phenotype. CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation.

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Cbfa1: a molecular switch in osteoblast biology.

P Ducy (2000)

During the past 4 years, our molecular understanding of osteoblast biology has made rapid progress due to the characterization of the function of one molecule, Cbfa1. This member of the runt/Cbfa family of transcription factors was first identified as the nuclear protein binding to an osteoblast-specific cis-acting element activating the expression of Osteocalcin, the most osteoblast-specific gene. Cbfa1 was then shown to regulate the expression of all the major genes expressed by osteoblasts. Consistent with this ability, genetic experiments identified Cbfa1 as a key regulator of osteoblast differentiation in vivo. Indeed, analysis of Cbfa1-deficient mice revealed that osteoblast differentiation is arrested in absence of Cbfa1, demonstrating both that it is required for this process and that no parallel pathway can overcome its absence. The importance of Cbfa1 in controlling osteoblast differentiation was further emphasized by the identification of Cbfa1 haploinsufficiency as the cause of cleidocranial dysplasia in humans and mice, a syndrome characterized by generalized bone defects. Lastly, Cbfa1 was shown to have a role beyond development and differentiation, regulating the rate of bone matrix deposition by differentiated osteoblasts. Thus, Cbfa1 is a critical gene not only for osteoblast differentiation but also for osteoblast function. These aspects, as well as the more recent progresses in understanding Cbfa1 biology, are the focuses of this review. Copyright 2000 Wiley-Liss, Inc.

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Author and article information

Contributors

Hong-Po Chang

Journal

Journal ID (nlm-ta): J Dent Sci

Journal ID (iso-abbrev): J Dent Sci

Title: Journal of Dental Sciences

Publisher: Association for Dental Sciences of the Republic of China

ISSN (Print): 1991-7902

ISSN (Electronic): 2213-8862

Publication date PMC-release: 19 October 2017

Publication date (Print): December 2017

Publication date (Electronic): 19 October 2017

Volume: 12

Issue: 4

Pages: 313-318

Affiliations

[a ]Department of Orthodontics, Dental Clinics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

[b ]School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

[c ]Department of Prosthodontics, Dental Clinics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

[d ]Department of Dentistry (Orthodontics), Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan

Author notes

[∗ ]Corresponding author. School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan. chang610004@ 123456gmail.com hopoch@ 123456kmu.edu.tw

Article

Publisher ID: S1991-7902(17)30100-9

DOI: 10.1016/j.jds.2017.07.002

PMC ID: 6395362

PubMed ID: 30895069

SO-VID: c2173c20-ddd0-4a7f-bf26-f9156f676982

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Craniofacial features of cleidocranial dysplasia

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Abstract

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Computational epistasis

Most cited references 36

Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia.

Cleidocranial dysplasia: clinical and molecular genetics.

Cbfa1: a molecular switch in osteoblast biology.

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