Dental malformations associated with biallelic MMP20 mutations.
Dental malformations associated with biallelic MMP20 mutations.
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与双等位 MMP20 突变相关的牙齿畸形。
DOI：
10.1002/mgg3.1307
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发表时间：
2020
影响因子：
2
通讯作者：
Simmer,Jame
中科院分区：
文献类型：
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作者：
Wang,Shih-Kai;Zhang,Hong;Chavez,MichaelB;Hu,Yuanyuan;Seymen,Figen;Koruyucu,Mine;Kasimoglu,Yelda;Colvin,ConnorD;Kolli,TamaraN;Tan,MichelleH;Wang,Yin-Lin;Lu,Pei-Ying;Kim,Jung-Wook;Foster,BrianL;Bartlett,JohnD;Simmer,Jame
背景基质金属肽酶20(MMP20)是一种进化保守的蛋白水解酶，在牙釉质形成过程中对釉质基质蛋白的加工至关重要。MMP20基因突变可导致人类常染色体隐性色素变性低变型成釉不全(AI2A2；OMIM#612529)。MMP20在成牙本质细胞和成釉细胞中均有表达，但其在牙本质形成过程中的作用尚不清楚。方法通过组织学、背散射扫描电子显微镜、微米CT和纳米硬度测试，鉴定了10个存在MMP20缺陷的AI家系、人类第三磨牙和/或MMP20−/−小鼠。4个致病变异体与编码MMP20类血粘蛋白(PEX)结构域的外显子相关，提示其具有必要的调节功能。突变的人牙釉质硬度在牙本质牙釉质交界处(DEJ)和釉质表面之间是最软的(正常的13%)。第三磨牙的扫描电子显微镜和微CT分析显示牙釉质和牙本质中的矿物质密度降低。接近DEJ的牙本质平均硬度为对照组的62%-69%。MMP20−/−小鼠牙本质的特性显示，牙本质厚度和矿化密度显著降低，前牙本质厚度一过性增加，提示牙本质基质分泌和矿化障碍。结论本研究扩大了MMP20致病突变的范围，为MMP20在牙本质形成过程中的功能提供了初步证据。
BackgroundMatrix metallopeptidase 20 (MMP20) is an evolutionarily conserved protease that is essential for processing enamel matrix proteins during dental enamel formation.MMP20mutations cause human autosomal recessive pigmented hypomaturation‐type amelogenesis imperfecta (AI2A2; OMIM #612529). MMP20 is expressed in both odontoblasts and ameloblasts, but its function during dentinogenesis is unclear.MethodsWe characterized 10 AI kindreds withMMP20defects, characterized human third molars and/orMmp20−/−mice by histology, Backscattered Scanning Electron Microscopy (bSEM), µCT, and nanohardness testing.ResultsWe identified six novelMMP20disease‐causing mutations. Four pathogenic variants were associated with exons encoding the MMP20 hemopexin‐like (PEX) domain, suggesting a necessary regulatory function. Mutant human enamel hardness was softest (13% of normal) midway between the dentinoenamel junction (DEJ) and the enamel surface. bSEM and µCT analyses of the third molars revealed reduced mineral density in both enamel and dentin. Dentin close to the DEJ showed an average hardness number 62%–69% of control. Characterization ofMmp20−/−mouse dentin revealed a significant reduction in dentin thickness and mineral density and a transient increase in predentin thickness, indicating disturbances in dentin matrix secretion and mineralization.ConclusionThese results expand the spectrum ofMMP20disease‐causing mutations and provide the first evidence for MMP20 function during dentin formation.