巨颌症致病基因SH3BP2及其对病变中破骨细胞的作用

巨颌症是一种少见的常染色体显性遗传病,现已明确其致病基因为SH3BP2。此基因突变导致SH3BP2蛋白功能的改变,从而引起病变中破骨细胞的病理性高活性表达,最终导致巨颌症骨质破坏的病理性改变。下面就SH3BP2基因的功能和SH3BP2基因对巨颌症疾病发生的调控作用以及与破骨细胞的联系作一综述。     

巨颌症致病基因SH3BP2突变体对成纤维细胞的增殖抑制作用研究

目的：观察过表达突变型SH3BP2（P．Asp419Gly）的单核细胞对颌骨成纤维细胞增殖的影响,探讨巨颌症病灶内纤维异常增殖的机制。方法：构建巨颌症致病基因SH3BP2突变（C．1256A〉G）载体,转染单核细胞系Raw264．7,筛选过表达稳定株;以过表达野生型SH3BP2的Raw264．7稳定株为对照。制备Raw264．7条件培养基,培养颌骨成纤维细胞并对比其生长状态。结果：成功建立过表达细胞系。突变型组条件培养基中成纤维细胞减少速率小于野生型组（P〈O．05）。结论：与野生型相比,突变型SH3BP2单核细胞对颌骨成纤维细胞生长抑制作用较弱,可能是巨颌症病灶常见纤维异常增殖的原因之一。     

巨颌症患者SH3BP2基因突变对NFATc1和SH3BP2蛋白表达的影响

目的分析SH3BP2基因点突变后,与其相关的信号转导通路发生的变化,探讨巨颌症发病的分子机制。方法采用免疫荧光技术检测巨颌症患者的活化T细胞核因子（nuclear factor of activated Tcells,NFAT）家族中的NFATc1及SH3BP2蛋白在细胞内的定位及表达含量的变化。结果巨颌症标本中NFATc1总体表达含量变化不明显,但发生了核内转位;SH3BP2在巨颌症组织中表达量增高。结论巨颌症致病基因SH3BP2发生点突变后,SH3BP2蛋白表达量可增多,并可导致NFATc1发生核内转位,这可能是导致巨颌症病变中破骨细胞被激活,形成骨吸收的重要机制。     

一个巨颌症家系SH3BP2基因的突变检测

目的了解国内巨颌症致病基因的突变情况.方法对一个家系的10位成员进行外周血基因组DNA的提取;用聚合酶链反应结合DNA直接测序的方法进行SH3BP2突变检测.结果该家系中的6位直系成员均存在SH3BP2基因第9外显子的单碱基错义突变,为G1505C,导致编码第415位氨基酸的密码子由CGA替换为CCA,其编码的氨基酸由精氨酸（Arg）变为脯氨酸（Pro）.结论SH3BP2基因的单碱基突变是引起这个巨颌症家系的致病突变.该突变与国外一学者发现的突变完全相同.     

过表达突变型SH3BP2基因的Raw 264.7细胞中纤维增殖相关基因的检测

目的:检测过表达野生型和突变型SH3BP2(p.Asp419Gly)基因的Raw264.7细胞株中表达差异基因,以明确与巨颌症纤维增殖相关的影响因素。方法:提取两种细胞株总RNA,进行基因芯片分析、数据库检索、RealTimePCR检测,最终确定纤维增殖相关基因。结果:找到表达差异基因共734个,上调基因313个,下调基因421个;综合基因芯片、数据库检索和RealtimePCR结果,发现4个与纤维异常增殖相关,分别为:CXCL10,IL10,Tnfrsf13b,Pf4。结论:发现4个纤维异常增殖相关基因,为进一步巨颌症纤维异常增殖的影响因素和机制研究奠定了基础。     

遗传性牙龈纤维瘤病致病基因机制研究进展

非综合征型遗传性牙龈纤维瘤病具有显著的遗传异质性,其致病基因及致病机制目前尚不明确;综合征型遗传性牙龈纤维瘤病,尽管大部分致病基因已知,但缺乏系统性整理及分析.本文对二者的致病基因及致病机制进行综述.     

luxS基因在细菌代谢组学中的相关功能研究进展

luxS基因广泛存在于多种致病菌中,为自身诱导分子-2形成的标志性基因,不但具有密度感应能力,在代谢组学相关方面也有着重要的作用.本文就luxS基因在活化甲基循环中的作用以及其在不同细菌硫代谢、口腔致病菌糖类代谢方面的研究进展作一综述.     

非综合征型先天缺牙致病基因和分子机制的研究进展

先天缺牙是牙齿发育过程中常见的牙数目发育异常,对患者的颌面部发育及美观和咀嚼功能产生严重的影响。根据有无伴发全身症状,先天缺牙可分为综合征型先天缺牙与非综合征型先天缺牙。近几年发现新的相关基因和新的突变位点及分子机制已成为目前非综合征型先天缺牙基因研究的主要方向。本文通过对近年来文献的回顾,对与非综合征型先天缺牙主要相关的Wnt/β-catenin信号通路、TGF-β/BMP信号通路、PAX9基因和MSX1基因、EDA/EDAR/NF-κb信号通路的分子机制以及相互调节的紧密联系进行综述,为未来先天缺牙的防治提供了新的理论基础。非综合征型先天缺牙致病基因的分子机制的研究目前甚少,对于其机制的精准探索将成为先天缺牙未来主要的研究方向之一。     

无汗/少汗型外胚叶发育不全家系致病基因的筛查

目的:探讨无汗/少汗型外胚叶发育不全(HED)家系的遗传方式及表型特点,并对家系致病基因进行筛查。方法:采用临床检查和家系调查的方法,对通过先证者法收集的HED家系进行遗传方式和临床表现分析。利用直接测序法对EDA、EDAR和EDARADD基因开放阅读框内外显子编码区及外显子-内含子接头区核苷酸序列进行分析。结果:收集到的家系为典型的无汗/少汗型外胚叶发育不全家系,先证者临床表现典型,毛发发育不良,头发、眉毛、睫毛稀疏;汗腺发育不良,无汗/少汗,体温随季节变化有明显改变;缺失多颗恒牙,并有乳牙滞留。家系内其他成员无明显异常表现。对EDA、EDAR和EDARADD基因开放阅读框的测序分析未找到致病突变。结论:本研究收集家系的患者临床症状明显,排除目前已知致病基因突变。     

Novel mutations in the SH3BP2 gene associated with sporadic central giant cell lesions and cherubism

Central giant cell lesion (CGCL) is a reactive bone lesion that occurs mainly in the mandible, characterized by the multinucleated osteoclast-like giant cells in a background of oval to spindle-shaped mononuclear cells. The etiology is unknown and occurs more commonly in young adults. Cherubism, a rare disease found predominantly in females has histologic characteristics indistinguishable from those of CGCL and is caused by mutations mostly present in exon 9 of the SH3BP2 gene. In this study, we investigated four cases of CGCL and one case of cherubism. DNA was extracted from peripheral blood and tumor tissue and all coding and flanking regions of the SH3BP2 amplified by PCR and directly sequenced to identify underlying mutations. Two novel mutations were found; a heterozygous missense mutation c.1442A>T (Q481L) in exon 11 in one sporadic case of CGCL and a heterozygous germline and tumor tissue missense mutation c.320C>T (T107M) in exon 4 in one patient with cherubism. These findings open a new window to investigate the possible relationship between the pathogenesis of the cherubism and CGCL.     

SH3BP2-encoding exons involved in cherubism are not associated with central giant cell granuloma

Central giant cell granuloma (CGCG) is a benign lesion with unpredictable biological behaviour ranging from a slow-growing asymptomatic swelling to an aggressive lesion associated with pain, bone and root resorption and also tooth displacement. The aetiology of the disease is unclear with controversies in the literature on whether it is mainly of reactional, inflammatory, infectious, neoplasic or genetic origin. To test the hypothesis that mutations in the SH3BP2 gene, as the principal cause of cherubism, are also responsible for, or at least associated with, giant cell lesions, 30 patients with CGCG were recruited for this study and subjected to analysis of germ line and/or somatic alterations. In the blood samples of nine patients, one codon alteration in exon 4 was found, but this alteration did not lead to changes at the amino acid level. In conclusion, if a primary genetic defect is the cause for CGCG it is either located in SH3BP2 gene exons not yet related to cherubism or in a different gene.     

A missense mutation in the SH3BP2 gene on chromosome 4p16.3 found in a case of nonfamilial cherubism.

OBJECTIVE: Cherubism is a rare hereditary multilocular cystic disease of the jaws, characterized by its typical appearance. Although nonfamilial cases have been reported, it is difficult to distinguish nonfamilial cherubism from central giant cell granuloma. Recent studies have revealed the point mutations in the SH3BP2 gene on chromosome 4p16.3 in cherubism families. In this article, the SH3BP2 gene in nonfamilial cherubism was examined. PATIENT: A 21-year-old Japanese woman with nonfamilial cherubism. INTERVENTIONS: Genomic DNA was purified from a blood sample obtained from the patient and used for direct sequencing. In addition, a sample of the lesion, resected during surgery, was used for histologic and immunohistochemical purposes. RESULTS: Genomic DNA sequencing found a Pro418Arg mutation in the SH3BP2 gene of the patient. In a histochemical analysis, the multinucleated giant cells proved to be strongly positive for PGM-1, KP-1, and tartrate-resistant acid phosphatase and faintly positive for osteopontin. CONCLUSIONS: The missense mutation Pro418Arg was identified in the SH3BP2 gene from a nonfamilial case of cherubism. DNA diagnosis may play a significant role in the identification of cherubism.     

Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw

Giant cell granulomas of the jaw (GCGJ) are non-familial, generally unilateral osteoclast-rich lesions that are histopathologically indistinguishable from cherubism. Cherubism is an autosomal dominant disease that is characterised by bilateral radiolucencies of the jaw, and caused by mutations that occur in SH3BP2 exon 10. The aim of the study was to screen lesional GCGJ tissue for SH3BP2 mutations. Lesional mononuclear stromal or spindle cells were microdissected from paraffin-embedded tissue from GCGJ, and DNA was then extracted and sequenced for SH3BP2 mutations associated with cherubism. No mutations were detected in 26 GCGJ (15 central, 11 peripheral), which indicated that people with GCGJ do not harbour cherubism-related germline SH3BP2 mutations, and that GCGJ do not harbour somatic SH3BP2 mutations. This suggests that cherubism and GCGJ arise on a different genetic background, and therefore detection of SH3BP2 mutations can be a useful means of distinguishing between them.     

DNA analysis of the SH3BP2 gene in patients with aggressive central giant cell granuloma

A mutation of the SH3BP2 gene is known to cause cherubism. As there are clinical and histopathological similarities between central giant cell granuloma and cherubism, we made a constitutional DNA analysis of the SH3BP2 gene in four patients with aggressive giant cell granuloma (having one or more of the following features pain, paraesthesia, rapid growth, or root resorption). We found no mutations in the SH3BP2 gene, which indicates that cherubism is a separate entity. However, a somatic mutation in a specific group of cells could cause the focal lesions in giant cell granuloma. Further DNA analysis of the tissue of giant cell granulomas therefore seems indicated.