Abstract:Background
Ameloblastin (AMBN) is a secreted matrix protein that is critical for the formation of dental enamel and is enamel‐specific with respect to its essential functions. Biallelic AMBN defects cause non‐syndromic autosomal recessive amelogenesis imperfecta. Homozygous Ambn mutant mice expressing an internally truncated AMBN protein deposit only a soft mineral crust on the surface of dentin.
Methods
We characterized a family with hypoplastic amelogenesis imperfecta caused by AMBN compound heterozygous mut… Show more
“…In addition, the enamel layer achieves its full thickness and normal contour by Level 3 in all three genotypes. This is very different from the bSEM results when a gene necessary for the secretory stage is affected and the enamel layer fails to expand significantly, as in amelogenin 34 , 35 , enamelin 36 , ameloblastin 37 , and matrix metallopeptidase 20 (MMP20) 28 , 38 null mice. Figure 6 bSEM of 7-wk Odaph +/+ , Odaph +/C41* , and Odaph C41*/C41* Mouse Mandibular Incisor Cross-Sections.…”
Mutations of Odontogenesis-Associated Phosphoprotein (ODAPH, OMIM *614829) cause autosomal recessive amelogenesis imperfecta, however, the function of ODAPH during amelogenesis is unknown. Here we characterized normal Odaph expression by in situ hybridization, generated Odaph truncation mice using CRISPR/Cas9 to replace the TGC codon encoding Cys41 into a TGA translation termination codon, and characterized and compared molar and incisor tooth formation in Odaph+/+, Odaph+/C41*, and OdaphC41*/C41* mice. We also searched genomes to determine when Odaph first appeared phylogenetically. We determined that tooth development in Odaph+/+ and Odaph+/C41* mice was indistinguishable in all respects, so the condition in mice is inherited in a recessive pattern, as it is in humans. Odaph is specifically expressed by ameloblasts starting with the onset of post-secretory transition and continues until mid-maturation. Based upon histological and ultrastructural analyses, we determined that the secretory stage of amelogenesis is not affected in OdaphC41*/C41* mice. The enamel layer achieves a normal shape and contour, normal thickness, and normal rod decussation. The fundamental problem in OdaphC41*/C41* mice starts during post-secretory transition, which fails to generate maturation stage ameloblasts. At the onset of what should be enamel maturation, a cyst forms that separates flattened ameloblasts from the enamel surface. The maturation stage fails completely.
“…In addition, the enamel layer achieves its full thickness and normal contour by Level 3 in all three genotypes. This is very different from the bSEM results when a gene necessary for the secretory stage is affected and the enamel layer fails to expand significantly, as in amelogenin 34 , 35 , enamelin 36 , ameloblastin 37 , and matrix metallopeptidase 20 (MMP20) 28 , 38 null mice. Figure 6 bSEM of 7-wk Odaph +/+ , Odaph +/C41* , and Odaph C41*/C41* Mouse Mandibular Incisor Cross-Sections.…”
Mutations of Odontogenesis-Associated Phosphoprotein (ODAPH, OMIM *614829) cause autosomal recessive amelogenesis imperfecta, however, the function of ODAPH during amelogenesis is unknown. Here we characterized normal Odaph expression by in situ hybridization, generated Odaph truncation mice using CRISPR/Cas9 to replace the TGC codon encoding Cys41 into a TGA translation termination codon, and characterized and compared molar and incisor tooth formation in Odaph+/+, Odaph+/C41*, and OdaphC41*/C41* mice. We also searched genomes to determine when Odaph first appeared phylogenetically. We determined that tooth development in Odaph+/+ and Odaph+/C41* mice was indistinguishable in all respects, so the condition in mice is inherited in a recessive pattern, as it is in humans. Odaph is specifically expressed by ameloblasts starting with the onset of post-secretory transition and continues until mid-maturation. Based upon histological and ultrastructural analyses, we determined that the secretory stage of amelogenesis is not affected in OdaphC41*/C41* mice. The enamel layer achieves a normal shape and contour, normal thickness, and normal rod decussation. The fundamental problem in OdaphC41*/C41* mice starts during post-secretory transition, which fails to generate maturation stage ameloblasts. At the onset of what should be enamel maturation, a cyst forms that separates flattened ameloblasts from the enamel surface. The maturation stage fails completely.
“…On the other hand, an increased amount of both intracellular and extracellular AMEL found in the mutant incisor might impede elongation and proper orientation of mineral ribbons. Interestingly, the numerous ectopic mineral depositions in the Acp4 mutant incisors and molars appear similar to those found in the Enam and Ambn null mice, although to a lesser extent 45 , 68 , 69 . Along with the finding that ACP4 localizes to the Tomes’ process, the above observations suggest that ACP4 is essential for both initiation and elongation of enamel mineral ribbons probably through regulating secretion or turnover of EMPs around mineralization front apparatus 69 , 70 .…”
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.
“…It is also conceivable, however, that AMEL arose in sarcopterygians and SCPP5 in actinopterygians. Studies of gene-disrupted mice showed that both AMBN and ENAM are necessary for enamel ribbon formation, the unique mineralization process of enamel, whereas AMEL is not ( Smith et al., 2016 ; Liang et al., 2019 ). Furthermore, a thin enamel can form in AMEL -deficient mice and in toothed whales that have deleterious mutations in AMEL , if both AMBN and ENAM are functional ( Gibson et al., 2001 ; Kawasaki et al., 2020 ).…”
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