Abstract
We identified a family in which pitted hypomineralized amelogenesis imperfecta (AI) with premature enamel failure segregated in an autosomal recessive fashion. Whole-exome sequencing revealed a missense mutation (c.586C>A, p.P196T) in the I-domain of integrin-β6 (ITGB6), which is consistently predicted to be pathogenic by all available programmes and is the only variant that segregates with the disease phenotype. Furthermore, a recent study revealed that mice lacking a functional allele of Itgb6 display a hypomaturation AI phenotype. Phenotypic characterization of affected human teeth in this study showed areas of abnormal prismatic organization, areas of low mineral density and severe abnormal surface pitting in the tooth's coronal portion. We suggest that the pathogenesis of this form of AI may be due to ineffective ligand binding of ITGB6 resulting in either compromised cell–matrix interaction or compromised ITGB6 activation of transforming growth factor-β (TGF-β) impacting indirectly on ameloblast–ameloblast interactions and proteolytic processing of extracellular matrix proteins via MMP20. This study adds to the list of genes mutated in AI and further highlights the importance of cell–matrix interactions during enamel formation.
Highlights
Enamel is the hardest human tissue and when formed correctly has the capacity to remain functional in to very old age
We suggest that the pathogenesis of this form of amelogenesis imperfecta (AI) may be due to ineffective ligand binding of ITGB6 resulting in either compromised cell – matrix interaction or compromised ITGB6 activation of transforming growth factor-b (TGF-b) impacting indirectly on ameloblast – ameloblast interactions and proteolytic processing of extracellular matrix proteins via MMP20
We identified a family of Pakistani origin segregating pitted hypomineralized AI in an autosomal recessive manner
Summary
Enamel is the hardest human tissue and when formed correctly has the capacity to remain functional in to very old age. The physical properties of mature enamel are a result of its high mineral content and the complex, though ordered, spatial inter-relationship and orientation of the enamel prisms. Ameloblasts grow in length and secrete an enamel matrix at their apical surface which forms the initial layer of aprismatic enamel. The highly organized interlocking prismatic pattern resulting from the concerted movement of ameloblast cohorts provides the structure that is key to the physical strength of the final enamel [5]. During the maturation stage, ameloblastmediated proteolytic destruction and removal (via secretion of the protease KLK4) of organic material from the matrix and ameloblast-mediated ion exchange are required for HAP crystals to grow in both thickness and width, until almost the entire tissue volume is occluded by mineral. By the end of the maturation stage, the newly formed enamel contains a mineral content of
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