Enamel defects in Acp4(R110C/R110C) mice and human ACP4 mutations

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Liang T., Wang S., Smith C., Zhang H., Hu Y., Seymen F., ...More

SCIENTIFIC REPORTS, vol.12, no.1, 2022 (SCI-Expanded, Scopus)

  • Publication Type: Article / Article
  • Volume: 12 Issue: 1
  • Publication Date: 2022
  • Doi Number: 10.1038/s41598-022-20684-9
  • Journal Name: SCIENTIFIC REPORTS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Open Archive Collection: AVESIS Open Access Collection
  • Istanbul University Affiliated: Yes

Abstract

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 Acp4(R110C) 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 (Acp4(R110C/R110C)) mice exhibited a thin layer of aplastic enamel with numerous ectopic mineralized nodules. Acp4(R110C/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.