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FAM20A Gene Mutation: Amelogenesis or Ectopic Mineralization?

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      Abstract

      Background and objective: FAM20A gene mutations result in enamel renal syndrome (ERS) associated with amelogenesis imperfecta (AI), nephrocalcinosis, gingival fibromatosis, and impaired tooth eruption. FAM20A would control the phosphorylation of enamel peptides and thus enamel mineralization. Here, we characterized the structure and chemical composition of unerupted tooth enamel from ERS patients and healthy subjects.

      Methods: Tooth sections were analyzed by Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), X-Ray Diffraction (XRD), and X-Ray Fluorescence (XRF).

      Results: SEM revealed that prisms were restricted to the inner-most enamel zones. The bulk of the mineralized matter covering the crown was formed by layers with varying electron-densities organized into lamellae and micronodules. Tissue porosity progressively increased at the periphery, ending with loose and unfused nanonodules also observed in the adjoining soft tissues. Thus, the enamel layer covering the dentin in all ERS patients (except a limited layer of enamel at the dentino-enamel junction) displayed an ultrastructural globular pattern similar to one observed in ectopic mineralization of soft tissue, notably in the gingiva of Fam20a knockout mice. XRD analysis confirmed the existence of alterations in crystallinity and composition (vs. sound enamel). XRF identified lower levels of calcium and phosphorus in ERS enamel. Finally, EDS confirmed the reduced amount of calcium in ERS enamel, which appeared similar to dentin.

      Conclusion: This study suggests that, after an initial normal start to amelogenesis, the bulk of the tissue covering coronal dentin would be formed by different mechanisms based on nano- to micro-nodule aggregation. This evocated ectopic mineralization process is known to intervene in several soft tissues in FAM20A gene mutant.

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      Most cited references 48

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      A multiplatform code for the analysis of energy-dispersive X-ray fluorescence spectra

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        The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification.

        Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2-Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D-rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.
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          Secreted kinase phosphorylates extracellular proteins that regulate biomineralization.

          Protein phosphorylation is a fundamental mechanism regulating nearly every aspect of cellular life. Several secreted proteins are phosphorylated, but the kinases responsible are unknown. We identified a family of atypical protein kinases that localize within the Golgi apparatus and are secreted. Fam20C appears to be the Golgi casein kinase that phosphorylates secretory pathway proteins within S-x-E motifs. Fam20C phosphorylates the caseins and several secreted proteins implicated in biomineralization, including the small integrin-binding ligand, N-linked glycoproteins (SIBLINGs). Consequently, mutations in Fam20C cause an osteosclerotic bone dysplasia in humans known as Raine syndrome. Fam20C is thus a protein kinase dedicated to the phosphorylation of extracellular proteins.
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            Author and article information

            Affiliations
            1Molecular Oral Pathophysiology, Cordeliers Research Center, UMRS 1138 Institut National de la Santé et de la Recherche Médicale, Paris-Descartes, Pierre-et-Marie-Curie, Paris-Diderot Universities Paris, France
            2Laboratoire de Physique des Solides, Centre National de la Recherche Scientifique, Univ. Paris-Sud, Université Paris-Saclay Orsay Cedex, France
            3Reference Center of Rare Buccal and Facial Malformations MAFACE-Rothschild Hospital, APHP Paris, France
            Author notes

            Edited by: Petros Papagerakis, University of Michigan, USA

            Reviewed by: Jung-Wook Kim, Seoul National University, South Korea; Hidemitsu Harada, Iwate Medical University, Japan; Amel Gritli-Linde, University of Gothenburg, Sweden

            *Correspondence: Arnaud Dessombz arnaud.dessombz@ 123456crc.jussieu.fr

            This article was submitted to Craniofacial Biology and Dental Research, a section of the journal Frontiers in Physiology

            †Co-first-authors.

            ‡Co-last-authors.

            Contributors
            Journal
            Front Physiol
            Front Physiol
            Front. Physiol.
            Frontiers in Physiology
            Frontiers Media S.A.
            1664-042X
            03 May 2017
            2017
            : 8
            5413562 10.3389/fphys.2017.00267
            Copyright © 2017 Lignon, Beres, Quentric, Rouzière, Weil, De La Dure-Molla, Naveau, Kozyraki, Dessombz and Berdal.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 4, Tables: 0, Equations: 0, References: 48, Pages: 8, Words: 6078
            Categories
            Physiology
            Original Research

            Anatomy & Physiology

            amelogenesis imperfecta, fam20a, rare disease, mineral, matrix biology

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