A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta.
A mutation in the mouse Amelx tri-tyrosyl domain results in impaired secretion of amelogenin and phenocopies human X-linked amelogenesis imperfecta.
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DOI：
10.1093/hmg/ddq001
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Dixon MJ
中科院分区：
文献类型：
--
作者：
Barron MJ;Brookes SJ;Kirkham J;Shore RC;Hunt C;Mironov A;Kingswell NJ;Maycock J;Shuttleworth CA;Dixon MJ
牙釉质发育不全症（AI）是一组广泛的临床和基因异质性遗传性牙釉质生物矿化缺陷。尽管发现了一些导致 AI 的基因突变，但确切的致病机制仍有待确定。我们采用多学科方法，在此描述了小鼠 Amelx 基因的一个错义突变，该突变导致牙釉质细胞外基质蛋白amelogenin 的三酪基结构域出现 Y → H 的置换。受影响动物的釉质表征与人类 X 连锁 AI 相似，在人类 X 连锁 AI 中也有类似突变的报道。受突变影响的动物存在严重的釉质生物矿化缺陷，发育中的釉质基质中缺乏全长釉质素蛋白，釉母细胞表型丧失，釉母细胞凋亡增加，并形成多细胞团块。我们提出的证据表明，受影响的釉母细胞能表达但不能分泌全长釉质素，从而导致内质网/高尔基体充血。免疫组化分析显示，在受影响的细胞中，amelogenin和ameloblastin都有积聚。在真核细胞系中联合转染 Ambn 和突变体 Amelx，与单独转染野生型 Amelx、突变体 Amelx 或 Ambn 或联合转染野生型 Amelx 和 Ambn 的细胞相比，也会发现细胞内异常和细胞毒性增加。我们推测，通过amelogenin三酪基基团介导的细胞内蛋白质与蛋白质之间的相互作用是支撑这种人工智能分子发病机制的关键机制因素。因此，这项研究成功地将人类 AI 的相关鼠类模型中的表型与潜在遗传病变联系起来。
Amelogenesis imperfecta (AI) describes a broad group of clinically and genetically heterogeneous inherited defects of dental enamel bio-mineralization. Despite identification of a number of genetic mutations underlying AI, the precise causal mechanisms have yet to be determined. Using a multi-disciplinary approach, we describe here a mis-sense mutation in the mouse Amelx gene resulting in a Y → H substitution in the tri-tyrosyl domain of the enamel extracellular matrix protein amelogenin. The enamel in affected animals phenocopies human X-linked AI where similar mutations have been reported. Animals affected by the mutation have severe defects of enamel bio-mineralization associated with absence of full-length amelogenin protein in the developing enamel matrix, loss of ameloblast phenotype, increased ameloblast apoptosis and formation of multi-cellular masses. We present evidence to demonstrate that affected ameloblasts express but fail to secrete full-length amelogenin leading to engorgement of the endoplasmic reticulum/Golgi apparatus. Immunohistochemical analysis revealed accumulations of both amelogenin and ameloblastin in affected cells. Co-transfection of Ambn and mutant Amelx in a eukaryotic cell line also revealed intracellular abnormalities and increased cytotoxicity compared with cells singly transfected with wild-type Amelx, mutant Amelx or Ambn or co-transfected with both wild-type Amelx and Ambn. We hypothesize that intracellular protein–protein interactions mediated via the amelogenin tri-tyrosyl motif are a key mechanistic factor underpinning the molecular pathogenesis in this example of AI. This study therefore successfully links phenotype with underlying genetic lesion in a relevant murine model for human AI.
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影响因子：
2.7
作者：
Hu, Jan C. -C.;Chun, Yong-Hee P.;Simmer, James P.
通讯作者：
Simmer, James P.
DOI：
10.1111/j.1600-0528.1986.tb01493.x
发表时间：
1986-02-01
影响因子：
2.3
作者：
BACKMAN, B;HOLM, AK
通讯作者：
HOLM, AK
影响因子：
3.5
作者：
Masuya, H;Shimizu, K;Shiroishi, T
通讯作者：
Shiroishi, T
影响因子：
3
作者：
Collier, PM;Sauk, JJ;Gibson, CW
通讯作者：
Gibson, CW
影响因子：
3.5
作者：
Barron, Martin J.;Brookes, Steven J.;Dixon, Michael J.
通讯作者：
Dixon, Michael J.