Enamel defects in Acp4(R110C/R110C) mice and human ACP4 mutations.
Enamel defects in Acp4(R110C/R110C) mice and human ACP4 mutations.
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DOI：
10.1038/s41598-022-20684-9
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发表时间：
2022-10-01
影响因子：
4.6
通讯作者：
Hu, Jan C. -C.
中科院分区：
文献类型：
--
作者：
Liang, Tian;Wang, Shih-Kai;Smith, Charles;Zhang, Hong;Hu, Yuanyuan;Seymen, Figen;Koruyucu, Mine;Kasimoglu, Yelda;Kim, Jung-Wook;Zhang, Chuhua;Saunders, Thomas L.;Simmer, James P.;Hu, Jan C. -C.
人酸性磷酸酶4(OMIM*606362)编码一种跨膜蛋白，属于组氨酸酸性磷酸酶家族。ACP4中的隐性突变导致非综合征型成釉发育不全(AI1J，OMIM#617297)。虽然ACP活性在发育中的牙齿中早就被检测到，但它在牙齿发育中的功能以及ACP4相关的AI的发病机制在很大程度上仍不清楚。在这里，我们鉴定了两个AI1J家系，并鉴定出一个新的致病突变：C.774_775del，p.Gly260Aspfs*29。为了研究ACP4在成釉过程中的作用，我们建立并鉴定了携带p.(Arg110Cys)功能缺失突变的Acp4R110C小鼠。小鼠Acp4蛋白在成釉细胞分泌期表达最强，主要定位于Tomes突起。而Acp4杂合子(Acp4+/R110C)小鼠没有表现出表型，而纯合子(Acp4R110C/R110C)小鼠的门牙和磨牙显示出一层薄薄的再生牙釉质，并有大量异位矿化结节。Acp4R110C/R110C成釉细胞最初看起来正常，但在分泌中期进行了病理检查。在超微结构上，矿化牙本质上可见散在的釉质带，但不能伸长，而是形成异常的针状晶体。由有缺陷的Tomes‘s突起的远端膜所积聚的有机基质的球形。这些结果表明，ACP4可能通过处理和调控矿化前器周围的釉质基质蛋白，在牙釉质的同位生长过程中发挥重要作用。
Human ACP4 (OMIM*606362) encodes a transmembrane protein that belongs to histidine acid phosphatase (ACP) family. Recessive mutations in ACP4 cause non-syndromic hypoplastic amelogenesis imperfecta (AI1J, OMIM#617297). While ACP activity has long been detected in developing teeth, its functions during tooth development and the pathogenesis of ACP4-associated AI remain largely unknown. Here, we characterized 2 AI1J families and identified a novel ACP4 disease-causing mutation: c.774_775del, p.Gly260Aspfs*29. To investigate the role of ACP4 during amelogenesis, we generated and characterized Acp4R110C mice that carry the p.(Arg110Cys) loss-of-function mutation. Mouse Acp4 expression was the strongest at secretory stage ameloblasts, and the protein localized primarily at Tomes’ processes. While Acp4 heterozygous (Acp4+/R110C) mice showed no phenotypes, incisors and molars of homozygous (Acp4R110C/R110C) mice exhibited a thin layer of aplastic enamel with numerous ectopic mineralized nodules. Acp4R110C/R110C ameloblasts appeared normal initially but underwent pathology at mid-way of secretory stage. Ultrastructurally, sporadic enamel ribbons grew on mineralized dentin but failed to elongate, and aberrant needle-like crystals formed instead. Globs of organic matrix accumulated by the distal membranes of defective Tomes’ processes. These results demonstrated a critical role for ACP4 in appositional growth of dental enamel probably by processing and regulating enamel matrix proteins around mineralization front apparatus.
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影响因子：
2
作者：
Hu Y;Smith CE;Richardson AS;Bartlett JD;Hu JC;Simmer JP
通讯作者：
Simmer JP
影响因子：
14.9
作者：
Abugessaisa I;Ramilowski JA;Lizio M;Severin J;Hasegawa A;Harshbarger J;Kondo A;Noguchi S;Yip CW;Ooi JLC;Tagami M;Hori F;Agrawal S;Hon CC;Cardon M;Ikeda S;Ono H;Bono H;Kato M;Hashimoto K;Bonetti A;Kato M;Kobayashi N;Shin J;de Hoon M;Hayashizaki Y;Carninci P;Kawaji H;Kasukawa T
通讯作者：
Kasukawa T
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
1.9
作者：
Hu Y;Hu JC;Smith CE;Bartlett JD;Simmer JP
通讯作者：
Simmer JP
影响因子：
4.6
作者：
Bartlett JD;Smith CE;Hu Y;Ikeda A;Strauss M;Liang T;Hsu YH;Trout AH;McComb DW;Freeman RC;Simmer JP;Hu JC
通讯作者：
Hu JC