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Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452-9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency. [ABSTRACT FROM AUTHOR]

Cleidocranial dysplasia (CCD; MIM 119600 ) is a rare autosomal-dominant inherited disorder that causes an abnormal skeletal genesis characterized by short stature, absent or delayed closure of cranial sutures, hypoplastic or absent clavicles, and dental anomalies, such as delayed tooth eruption of permanent teeth, hypodontia, and supernumerary teeth. It has been demonstrated that hypomorphic or haploinsufficiency of the runt related transcription factor 2 ( RUNX2/CBFA1 ) gene is causative for CCD. RUNX2 encodes an osteoblast-specific transcription factor, which recognizes specific DNA sequences via the runt domain, and has an important role in the differentiation of osteoblasts and the maturation of chondrocytes. In this study we describe a case of a 9-year-old Japanese male with CCD who carries a novel mutation in the RUNX2/CBFA1 gene (c.473c>a) that resulted in an amino acid substitution (p.A158E) in the runt domain of the gene product. Although A158E RUNX2 showed stable exogenous expression in transfected COS7 cells and a normal nuclear localization pattern, it did not show transcriptional activity in a reporter assay. This indicates that the A158E mutation in RUNX2 is causal for the CCD in our current case. [ABSTRACT FROM AUTHOR]

Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Cytomegalovirus (CMV) commonly infects immunocompetent as well as immunocompromised hosts. The latter include recipients of organ transplants or immunosuppression therapy, and those with hematologic malignancies. The most common manifestation of a CMV infection of the gastrointestinal tract including the oral mucosa is ulceration. Up to now, there have been several reports of CMV infection in the oral mucosa resulting in mucosal ulceration. CMV infections producing a mass lesion as pseudotumoral in appearance have rarely been reported in the literature. There are a few reports of CMV pseudotumors in the head and neck. Here we report a case of intraoral pseudotumors caused by localized CMV infection in a patient who received a bone marrow transplantation (BMT). Although a lesion of this nature is rare, we must bear in mind the possibility of a CMV infection when we examine a patient who has received BMT with an oral mass-like lesion. [Copyright &y& Elsevier]