Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contact Us Login 
An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists

Year : 2007  |  Volume : 11  |  Issue : 1  |  Page : 42-44

Review of Scientific Articles

1 Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College, Chennai, India
2 Department of Microbiology, Meenakshi Ammal Dental College, Chennai, India

Correspondence Address:
G Sivakumar
Department of Oral and Maxillofacial Pathology, Meenakshi Ammal Dental College, Chennai
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-029X.33965

Rights and Permissions


How to cite this article:
Sivakumar G, Kavitha B, Priyadharshini V, Saraswathi T R. Review of Scientific Articles. J Oral Maxillofac Pathol 2007;11:42-4

How to cite this URL:
Sivakumar G, Kavitha B, Priyadharshini V, Saraswathi T R. Review of Scientific Articles. J Oral Maxillofac Pathol [serial online] 2007 [cited 2020 Mar 30];11:42-4. Available from: http://www.jomfp.in/text.asp?2007/11/1/42/33965

Novel Msx1 frameshift causes autosomal-dominant oligodontia

J Dent Res 85(3): 267-271, 2006

Msx1 is a homeobox gene involved in numerous epithelial-mesenchymal interactions during vertebrate embryogenesis, and appears to be incredibly significant during early tooth development. It has been suggested that Msx1 gene exerts both synergistic and antagonistic effect on various biomolecules involved in tooth formation. For example, deficiency of Msx1 expression reduces the expression of downstream signaling molecules, such as Bone Morphogenetic Protein 4 (Bmp4), and transcription factors like Lef1. Msx1 produces antagonistic effect with several other transcription factors, such as Dlx2 and Dlx5 , Lhx2, Pax3 , Pax9 . Hence, tooth agenesis could be associated with the expression of this gene.

Kim et al., have reported an Msx1 frameshift mutation in the affected members of a kindred with autosomal-dominant oligodontia without clefting or nail dysplasia. The mutation involves duplication of guanine at nucleotide position 62 in exon 1 of Msx1 gene which introduced 146 novel amino acids following the first 21 amino acids, thus altering the normal protein sequence from Gly22 through Thr297. This Msx1 mutation is associated with the absence of multiple permanent teeth, including all second bicuspids and mandibular central incisors. The sequence variation was considered to be a rare event since the same result was not observed in control groups or individuals with cleft lip or palate. Thus investigators reported that dominant phenotype of partial tooth agenesis is probably due to haploinsufficiency.

Phenotypic analysis revealed Msx1 and Pax9 kindred's have a high, but equal, probability of missing third molars, so the absence of third molars is not a useful indicator of which gene (Msx1 or Pax9) is likely to be affected in a given kindred. Consequently, they demonstrated that teeth most likely to be absent in Msx1-deficient kindred's were the maxillary and mandibular second bicuspids (91-97%), and the maxillary first bicuspids (75%). Therefore, the developmental absence of maxillary and mandibular second bicuspids and maxillary first bicuspids, with most mandibular first bicuspids retained, appears to be the pattern of tooth agenesis that best indicates the presence of an Msx1 mutation. In contrast, patients with Pax9 mutations typically show agenesis of almost all of their molars, with the absence of second molars best distinguishing them from persons with Msx1 defects.

The human KROX-26/ ZNF22 gene is expressed at sites of tooth formation and maps to the locus for permanent tooth agenesis (He-Zhao deficiency)

J Dent Res 82(12):1002-1007, 2003

A huge array of transcription factors is found to be involved in the process of odontogenesis. One among them is C 2 H 2 zinc finger gene family the largest class of transcription factors in mammalian genome. The role of zinc finger transcription factors in the regulation of gene expression during tooth development and specification of individual tooth cell phenotypes has been extensively investigated. Krox-26 , a kruppel-like zinc finger repeat is expressed predominantly in developing craniofacial skeletogenic and dental structures, particularly in secretory-stage ameloblasts. Studies conducted by Gao et al ., aimed at the identification, characterization of Krox-26 gene in humans, with a special emphasize on the expression pattern of the gene in the developing dental tissues and its chromosome location.

The genomic locus of the KROX-26 gene was determined by fluorescence in situ hybridization (FISH) on metaphase chromosome spreads. A single hybridization signal on both alleles of chromosome 10 was fine-mapped to the long arm of the chromosome at 10q11.21. Cloning and sequencing of Krox-26 gene revealed a protein of molecular weight 25915.4 Daltons with a predicted isoelectric point of 10.06. The accession number assigned to human Krox-26 nucleotide sequence is AY137767. The cellular expression of Krox-26 mRNA was assessed by in situ hybridization in 12-week-old embryonic tissues and by northern blotting in adult tissues.

Analysis of embryonic tissue with cRNA probes revealed expression of the gene in specific areas like dental epithelium of maxillary molar tooth organs, tongue epithelium, tongue muscle and osteoblasts of craniofacial bone. The adult tissues revealed the existence of a single 2.4-kb mRNA transcript, which is most highly expressed in mesoderm-derived tissues such as skeletal muscle, heart, kidney, and liver with intermediate expression levels observed in spleen, thymus, and brain. Expression levels in endoderm derived tissues such as intestine and colon were found to be relatively low. These results expound the significance of Krox-26 in tooth development. Further support was provided to elucidate the potential involvement of Krox-26 in tooth development by locating the Krox-26 gene close to the genetic locus for permanent tooth agenesis in humans (He-Zhao deficiency) whose gene locus was mapped to chromosome 10q11.2. Thus this chromosomal region contains other potential candidate genes, including the Wnt antagonist, Dickkopf-1 and a cluster of other, poorly characterized zinc finger genes.

Dentonin, a fragment of MEPE, enhanced dental pulp stem cell proliferation

J Dent Res 83(6): 496-499, 2004

Dentin mineralization is supposed to be directed by noncollagenous proteins such as matrix extracellular phosphoglycoprotein (MEPE) which is a novel protein found in human bone and dental tissues. MEPE is a related member of bone/dentin SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) family and mapped to the locus 4q21.1. Genes coding for SIBLING family are clustered at chromosome 4q, which is considered to be a critical loci for dentinogenesis imperfecta types II and III, and dentin dysplasia type II. This fact leads to the search for bioactive fragment of MEPE which resulted in the synthesis of dentonin, a 23-amino-acid residue that corresponds to region 242-264 of human MEPE.

Studies reported that dentonin has an inherent property to enhance DPSC (Dental pulp stem cell) proliferation. Further analysis of the effect of dentonin on cell-cycle-related genes showed a down-regulation of p16. This down-regulation activates various intermediate factors that are responsible for transcription of target genes which aids in the passage through G1/S restriction point, thus promoting cell proliferation. Dentonin peptide (TDLQERGDNDISPFSGDGQPFKD) contains the RGD integrin binding motif, and SGDG glycosaminoglycan-binding motif, which was shown to support bone formation and osteoblast proliferation. The maximal mitogenic activity of dentonin required the presence of an intact RGD and SGDG, as shown by a reduction in activity when either of these motifs was altered.

Addition of dentonin to DPSCs resulted in a significantly increased rate of cell proliferation. Alteration of SGDG motif resulted in significantly reduced mitogenic activity whereas alteration of RGD motif resulted in greater variability of response relating to increased concentrations of dentonin and DPSC proliferation. Cell-cycle gene SuperArray showed increased expression of nearly 7 genes with a two-fold down regulation of p16, an inhibitor of CDK4 in DPSCs. Ubiquitin protein ligase E3A (E6-AP) and human ubiquitin-related protein SUMO-1 mRNA were also found to be up-regulated in dentonin treated cells. Another vital consequence of this study is the fact that dentonin prop ups cell proliferation leaving the differentiation of DPSC undisturbed. Dentonin may effectively stimulate DPSC proliferation in vivo, and consequently enhance the ability of injured pulp to survive trauma such as occurs in dental restorations. Hence the results provided suggest the potential of Dentonin or AC-100 which would be a key to the field of reparative dentistry.

Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein 2

J Dent Res 83(8):590-595, 2004

Bone morphogenetic proteins (BMPs) have long been implicated in the development of tooth and increased expression of BMP2 is found during the terminal differentiation of odontoblasts. BMP2 has shown to induce a large amount of reparative dentin on the amputated pulp in vivo. It has been suggested that BMP2 may regulate the differentiation of pulp cells into odontoblastic lineage and stimulate reparative dentin formation. Iohara et al., has compared the efficacy of BMP2 on the differentiation of pulp cells into odontoblasts with the aid of pellet culture system.

Morphological and molecular biological evaluations were performed to examine the efficacy of BMP2 in pellet cultures. Though BMP2 was not found to affect cell proliferation, it exerted significant effect on the differentiation of DPSCs. An extensive osteodentin formation was observed in recombinant human BMP2-treated pellet cultures. Alkaline phosphatase activity and α (I) collagen was increased by BMP2. Quantitative analyses demonstrated that the amount of collagen fibers was significantly higher in BMP2-treated pellet. Relative expressions of Dmp1 , Dspp , enamelysin , Phex , and Cbfa3 in the BMP2-treated pellet were 7.4, 2.4, 6.0, 11.7, and 5.5 times more, respectively, compared with expressions in non-treated pellet. Mineralization was also found to be intense. These findings demonstrate that BMP2 stimulated differentiation of pulp cells into the odontoblastic lineage. This study substantiates the fact that pellet culture system allowed for better responsiveness of pulp cells to rhBMP2 when compared to monolayer culture.

The effectiveness of pellets treated with rhBMP2 in dentin regeneration was also investigated in vivo. Autogenous transplantation of recombinant BMP2 pellets was performed on the amputated pulp of immunocompromised mice. Large amounts of osteodentin were seen in rhBMP2-treated pellet, in contrast to non-treated pellet. A few osteodentinocytes in osteodentin and odontoblast-like cells with long processes attached to osteodentin to tubular dentin were observed. This research opens up a novel path to ex vivo cell therapy with an advantage that cultured tissue stem/progenitor cells can be implanted after differentiation into odontoblasts which might result in copious amounts of reparative dentin that will quench the long-term goal of biological regenerative endodontic therapy.

A nonsense mutation in MSX1 causes witkop syndrome

Hum. Genet. 69:67-74, 2001

Witkop syndrome, also known as "tooth and nail syndrome" (TNS) or "nail dysgenesis and hypodontia" is a rare autosomal dominant disorder which belongs to ectodermal dysplasia (EDs) type, characterized by defects in at least two ectodermally derived organs. TNS can be distinguished from other types of EDs by the fact that the abnormalities involve only teeth and nails. An attempt was made to spot the gene and the type of mutation responsible for Witkop syndrome which led to the identification of MsxI a candidate gene for tooth agenesis. Both genetic and histological analysis was performed to confirm this phenotype.

Linkage analysis was used to draw an association between TNS and markers surrounding the MSXI locus which showed a nonsense mutation (S202X) in MSX1 . On the basis of the data obtained from human family affected with TNS and Msx1-knockout mice, a conclusion was drawn stating that a nonsense mutation in MSXI is responsible for TNS. Experimental evidence ascertains that a nonsense mutation in the homeodomain of MSXI is responsible for TNS in a three-generation family. This result is based on several findings, first, there is complete cosegregation between the 605(C→ A) nucleotide substitution in the TNS phenotype family. Second, the expression domains of MsxI in developing teeth and forming nail beds of mice correlate with the tooth and nail defects in TNS. Third, MsxI-null mice exhibit tooth agenesis and defective nail plates, a phenotype that is similar to that of the family with TNS. Finally, a transversion substitutes a stop codon at amino acid position 37 in place of serine of the homeodomain, which produces a pruned protein. The putative missing part of the protein is known to be important for protein stability (helix II) and DNA binding (helix III), therefore the truncated protein, which lacks part of the homeodomain and entire C-terminal region, is not properly folded, unstable, or is unable to bind to DNA. Since S202X MsxI has an incomplete homeodomain that is required for DNA binding, it is likely that, even if S202X MsxI is synthesized as a stable protein fragment, it cannot effectively bind to DNA. Thus the investigators hypothesize that the S202X mutation produces a dominant phenotype of TNS through haploinsufficiency.

Novel mutation of the initiation codon of PAX9 causes oligodontia

J Dent Res 84(1):43-47, 2005

Oligodontia is a rare condition that can occur in association with genetic syndromes, or as a non-syndromic isolated familial trait, or as a sporadic finding. Many candidate genes have been found to be associated with tooth agenesis. This study focuses on a novel mutation in the initiation codon of Pax9 that has been identified and suggested to be responsible for non-syndromic oligodontia in one family. Pax9 is situated on chromosome 14 and belongs to the PAX gene family, which encodes a group of transcription factors that play a role in early development. PAX proteins are defined by the presence of a DNA-binding domain, the 'paired domain', which makes sequence-specific contact with DNA.

Pedigree analysis showed autosomal-dominant type of inheritance and oligodontia could be traced in four generations accompanied with myopia in three generations. The pedigree showed an autosomal-dominant transmission of both the gene for myopia and the gene for oligodontia. Therefore, confirming the fact that proband showed non-syndromic oligodontia. Orthopantomographic analysis revealed that both the proband and father had missing teeth in the primary dentition. The proband lacked all permanent molars, all second premolars, and upper first premolars. Both upper lateral incisors were peg-shaped, and upper permanent canines and lower first premolars had an abnormal crown shape. The affected father lacked all permanent molars, second premolars, upper first premolars, upper permanent canines, one upper lateral incisor (possibly due to extraction), and both lower first permanent incisors

A number of mutations have already been identified in the Pax gene, which includes nonsense, missense, frameshift and deletion types. The type of mutation found in family taken up for the study was a transition mutation in AUG initiation codon of Pax9 in exon 1. This heterozygous A-G mutation was observed based on the sequencing results with both the autoradiographic detection method and with dye terminator chemistry. Mutation in the initiation codon of Pax9 causes severe or complete inhibition of Pax9 translation at one allele, resulting in a reduced amount of Pax9 transcription factor. Thus a comprehensive knowledge on the structure, sequence and function of genes involved in tooth development is essential to trace numerous inherited dental abnormalities.


Print this article  Email this article


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Article in PDF (93 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

 Article Access Statistics
    PDF Downloaded505    
    Comments [Add]    

Recommend this journal

Journal of Oral and Maxillofacial Pathology | Published by Wolters Kluwer - Medknow
Online since 15th Aug, 2007