Multiple previous reports confirm that several missense alleles of MSX1 exhibit Mendelian inheritance of an oligodontia phenotype (agenesis of more than six secondary teeth besides third molars). However, the extent to which missense MSX1 alleles contribute to common, multifactorial disorders is less certain. It is still not yet clear whether multiple non-synonomous MSX1-coding variants identified among patients with oral clefting are merely neutral polymorphisms or whether any of these might represent real mutations with mild effects. The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate. Candidate gene sequencing within a patient cohort demonstrating mild tooth agenesis (loss of six or less secondary teeth besides third molars, hypodontia), secondarily identified this same MSX1 variant, functioning as a mildly deleterious, moderately penetrant allele. Four of five heterozygous R151S individuals from one Japanese family exhibited the hypodontia phenotype. The in vitro functional assays of the variant protein display partial repression activity with normal nuclear localization. These data establish that the MSX1-R151S allele is a low-frequency, mildly deleterious allele for familial hypodontia that alone is insufficient to cause oral facial clefting. Yet, as this work also establishes its hypomorphic nature, it suggests that it may in fact contribute to the likelihood of common birth disorder phenotypes, such as partial tooth agenesis and oral facial clefting. Nevertheless, the exact mechanism in which differential pleiotropy is manifested will need further and deeper clinical and functional analyses.
Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% [95% confidence interval (CI): 6.1-7.7%] and 0.1% (95% CI: 0.04-0.3%), respectively, and sibling recurrence risk of these were 24.5% (95% CI: 13.8-38.3%) and 43.8% (95% CI: 26.4-62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides.
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.
HANADA Hiroaki・KUROKAWA Yoshiya・FUJIWARA Shigeyoshi : Plasmablastic lymphoma (PBL) was first reported in 1997 as a non-Hodgkin' s lymphoma with a poor prognosis that occurred in the oral cavity of some human immunodeficiency virus (HIV)-positive patients. In 2008, it was added to the WHO classification as a type of aggressive B-cell lymphoma that can also occur in extranodal sites of elderly or immunocompromised patients. As half of the cases are related to Epstein-Barr virus (EBV) infection and categorized as EBV-associated lymphoproliferative disorders. We report a case of EBV-positive PBL that occurred in the mandibular gingiva of an HIV-negative patient. The patient was an 87-year-old man with a mass in the gingiva surrounding the second left mandibular molar. A biopsy revealed that the lesion was EBV-positive PBL. Serologically, HIV antibody was negative. The patient underwent radiation therapy (50 Gy) , which led to a completely positive response. After treatment, no recurrence was detected. Three years one month after treatment, dehydration led to a decrease in the level of consciousness and the resulting deterioration of general condition, and the patient died one month later. : plasmablastic lymphoma (形質芽細胞性リンパ腫) , EBV-positive (EBV 陽性) , mandibular gingiva(下顎 歯肉) , radiation therapy (放射線療法) 姫路赤十字病院歯科口腔外科 (主任:藤原成祥部長) Department of Oral and Maxillofacial Surgery, Himeji Red Cross Hospital
Objective-Identification of the breakpoints of disease-associated chromosome rearrangements can provide informative clues to a positional cloning approach for genes responsible for inherited diseases. Recently, we found a three-generation Japanese family segregating balanced chromosome translocation t(9;17)(q32;q12). One of the subjects had cleft lip and palate. We examined whether regions near the breakpoint could be associated with cleft lip and/or palate.Methods-We determined the breakpoints involved in the translocation by fluorescence in situ hybridization analysis and subsequent long-range polymerase chain reaction. In order to study the role of these disrupted regions in nonsyndromic cleft lip and/or palate, we performed mutation analysis and a haplotype-based transmission disequilibrium test using tagging single-nucleotide polymorphisms in the flanking regions of the breakpoints in white and Filipino nonsyndromic cleft lip and/or palate populations.Results-Sequence analysis demonstrated that two genes, SLC31A1 (solute carrier family 31 member 1) on chromosome 9 and CCL2 (chemokine ligand 2) on chromosome 17, were rearranged with the breaks occurring within their introns. It is interesting that SLC31A1 lies closed to BSPRY (B-box and SPRY domain), which is a candidate for involvement with cleft lip and/or palate. Some of the variants in BSPRY and CCL2 showed significant p values in the cleft lip and/or palate population compared with the control population. There was also statistically significant evidence of transmission distortion for haplotypes on both chromosomes 9 and 17.Conclusions-The data support previous reports that genes on chromosomal regions of 9q and 17q play an important role in facial development.
We report on a 65-year-old woman with primary squamous cell carcinoma of the sublingual gland. She consulted our department because of a painless mass of the left side of the oral floor. The results of a biopsy were squamous cell carcinoma or mucoepidermoid carcinoma. The tentative diagnosis was a malignant tumor of the left sublingual gland. Radical neck dissection, tumorectomy, and reconstruction were performed. Histopathological examination suggested squamous cell carcinoma. Systemic investigation revealed no tumors of other organs; the possibility of a metastatic tumor was ruled out. Because the tumor was localized in the sublingual gland, the diagnosis was primary squamous cell carcinoma of the sublingual gland. This type of carcinoma is rare. To date, the course has been favorable. However, squamous cell carcinoma of the salivary gland has a poor prognosis; follow-up should be continued in the future.
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