Abstract
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.
Highlights
C4orf[26] (Chromosome 4 open reading frame 26) was unknown to enamel scientists until geneticists found pathogenic variants in the gene that caused autosomal recessive inherited enamel defects in humans[1,2]
During the secretory stage enamel ribbons initiate on the surface of dentin and elongate with continued enamel matrix secretion and assembly to establish the full thickness of the enamel layer
The signal was low, it was specific for ameloblasts starting at the onset of ameloblast transition and continuing throughout early maturation stage
Summary
C4orf[26] (Chromosome 4 open reading frame 26) was unknown to enamel scientists until geneticists found pathogenic variants in the gene that caused autosomal recessive inherited enamel defects in humans[1,2]. Human ODAPH encodes a protein of 130 amino acids, including a 23 amino acid signal peptide and a secreted protein of 107 amino acids, which includes 19 prolines, 3 cysteines and multiple serines in context for phosphorylation by the Golgi Casein Kinase complex[4]. This kinase complex includes FAM20A5 and FAM20C6 and catalyzes functionally critical phosphorylations on three other secreted enamel matrix proteins: e namelin7,8, ameloblastin[9], and amelogenin[10]. Disturbances to tooth formation that occur during the secretory stage generally reduce the thickness of the enamel layer, causing enamel h ypoplasia[22]. Disturbances to tooth formation that occur during the maturation stage generally cause enamel hypomineralization, reducing the hardness of the enamel layer[22]
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