Liang, TianWang, Shih-KaiSmith, CharlesZhang, HongHu, YuanyuanSeymen, FigenKoruyucu, MineKasımoğlu, YeldaKim, Jung-wookZhang, ChuhuaSaunders, Thomas L.Simmer, James P.Hu, Jan C-C.2022-10-032022-10-032022Liang, T., Wang, S. K., Smith, C., Zhang, H., Hu, Y., Seymen, F., Koruyucu, M., Kasımoğlu, Y., Kasımoğlu, Y., Kim, J.-W., Zhang, C., Saunders, T. L., Simmer, J. P., Hu, J. C-C. (2022). Enamel defects in Acp4R110C/R110C mice and human ACP4 mutations. Scientific Reports, 12(1).https://hdl.handle.net/20.500.12939/2973Human 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.eninfo:eu-repo/semantics/openAccessACP4Article1212-s2.0-85139158485Q1WOS:000862559400028Q1