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<p>Defects in <i>Odontogenesis-Associated Phosphoprotein</i> (<i>ODAPH</i>) cause autosomal recessive non-syndromic amelogenesis imperfecta (AI; OMIM #614832). We present a 14-year-old boy with delayed tooth eruption and generalized soft and yellow enamel. The proband’s parents and two siblings were unaffected. Whole exome analyses identified the AI-causing homozygous <i>ODAPH</i> truncation mutation (p.Arg77*) in the proband. Both unaffected parents and one sibling were heterozygous for this change. The other sibling had the reference sequence. To better understand the role of ODAPH in normal amelogenesis and resolve conflicting reports of ODAPH expression and function during postsecretory transition (PST), we performed comprehensive Focused-Ion Beam Scanning Electron Microscopy analyses of continuously growing mandibular incisors from one wild-type and two <i>Odaph</i><sup>C41*/C41*</sup> mice. Montages of sagittal sections were constructed using 5000 × images covering the surface enamel, ameloblasts, stratum intermedium and papillary layer during late secretory, PST, and early maturation stages. <i>Odaph</i><sup>C41*/C41*</sup> ameloblasts completed the secretory stage showing no evidence of pathology. Dramatic histological differences between wild-type and <i>Odaph</i><sup>C41*/C41*</sup> ameloblasts were observed during postsecretory transition closely preceding the onset of cyst formation in <i>Odaph</i><sup>C41*/C41*</sup> ameloblasts. PST ameloblasts show marked abnormalities, including loss of polarity (nucleus moves distally), disrupted cellular organization, indistinct cell boundaries and rapid reduction in cell height. During PST and early maturation, a dark line indicative of a basal lamina is apparent in the superficial enamel, but it fails to maintain attachment with the ameloblast distal membrane, and a cyst forms between the enamel surface and the overlying flattened ameloblasts, which eliminates the entire maturation stage of amelogenesis. Immunohistochemistry of a Day 12 mandibular incisor detected ODAPH protein in PST and the maturation stage ameloloblasts, and concentrated along the basement membrane. We conclude that ODAPH is required for a successful transition into the maturation stage of amelogenesis. Loss of ODAPH function results in hypomineralized amelogenesis imperfecta.</p>

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ODAPH (p.Arg77*) Phenotype and Onset of Ameloblast Pathology During Postsecretory Transition Demonstrated by FIB-SEM Analyses of OdaphC41*/C41* Mice

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  • 发表日期：

    2026年7月3日

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  • Jan C.-C. Hu,
  • Charles E. Smith,
  • Hong Zhang,
  • Yuanyuan Hu,
  • Tian Liang,
  • Shih-Kai Wang,
  • Kuan Yu Chu,
  • Evans H. Brown,
  • James P. Simmer

摘要

Defects in Odontogenesis-Associated Phosphoprotein (ODAPH) cause autosomal recessive non-syndromic amelogenesis imperfecta (AI; OMIM #614832). We present a 14-year-old boy with delayed tooth eruption and generalized soft and yellow enamel. The proband’s parents and two siblings were unaffected. Whole exome analyses identified the AI-causing homozygous ODAPH truncation mutation (p.Arg77*) in the proband. Both unaffected parents and one sibling were heterozygous for this change. The other sibling had the reference sequence. To better understand the role of ODAPH in normal amelogenesis and resolve conflicting reports of ODAPH expression and function during postsecretory transition (PST), we performed comprehensive Focused-Ion Beam Scanning Electron Microscopy analyses of continuously growing mandibular incisors from one wild-type and two OdaphC41*/C41* mice. Montages of sagittal sections were constructed using 5000 × images covering the surface enamel, ameloblasts, stratum intermedium and papillary layer during late secretory, PST, and early maturation stages. OdaphC41*/C41* ameloblasts completed the secretory stage showing no evidence of pathology. Dramatic histological differences between wild-type and OdaphC41*/C41* ameloblasts were observed during postsecretory transition closely preceding the onset of cyst formation in OdaphC41*/C41* ameloblasts. PST ameloblasts show marked abnormalities, including loss of polarity (nucleus moves distally), disrupted cellular organization, indistinct cell boundaries and rapid reduction in cell height. During PST and early maturation, a dark line indicative of a basal lamina is apparent in the superficial enamel, but it fails to maintain attachment with the ameloblast distal membrane, and a cyst forms between the enamel surface and the overlying flattened ameloblasts, which eliminates the entire maturation stage of amelogenesis. Immunohistochemistry of a Day 12 mandibular incisor detected ODAPH protein in PST and the maturation stage ameloloblasts, and concentrated along the basement membrane. We conclude that ODAPH is required for a successful transition into the maturation stage of amelogenesis. Loss of ODAPH function results in hypomineralized amelogenesis imperfecta.