Abstract
Despite much progress in understanding the genetics of syndromic tooth agenesis (TA), the causes of the most common, isolated TA remain elusive. Recent studies have identified novel genes and variants contributing to the etiology of TA, and revealed new pathways in which tooth development genes belong. Further, the use of new research approaches including next-generation sequencing has provided increased evidence supporting an oligogenic inheritance model for TA, and may explain the phenotypic variability of the condition. In this review, we present current knowledge about the genetic mechanisms underlying syndromic and isolated TA in humans, and highlight the value of incorporating next-generation sequencing approaches to identify causative and/or modifier genes that contribute to the etiology of TA.
Highlights
Tooth development requires a sequential and reciprocal series of signaling interactions between the oral epithelium and the neural crest-derived mesenchyme, which are under strict genetic control by a number of signaling molecules and their downstream signaling pathways
Van der Woude syndrome (VWS) is caused by mutations in the IRF6 gene that encodes a transcription factor highly expressed during craniofacial development and a regulator of keratinocyte proliferation and differentiation [57]
Additional genes in the NF-kB pathway include NEMO, an important pathway modulator, and TRAF6 (TNF receptor associated factor 6), little is known about the exact roles of these genes in tooth development and variations in these two genes were reported in individuals with syndromic Tooth agenesis (TA) [4]
Summary
Tooth development requires a sequential and reciprocal series of signaling interactions between the oral epithelium and the neural crest-derived mesenchyme, which are under strict genetic control by a number of signaling molecules and their downstream signaling pathways During these stages, the continuous interplay of inductive signals between epithelia and mesenchyme in a precisely organized manner results in the formation of distinct and highly specialized structures, such as incisor, canine, premolar and molar teeth [1]. Epigenetic regulation affecting a network of interconnected signaling pathways that included tooth development was suggested to play a role in the etiology of TA [9] New technologies such as next-generation sequencing have proven to be valuable tools in the identification of novel TA genes and variants, and begun to elucidate the genetic defects responsible for this condition [10,11]. We present new perspectives on the potential molecular mechanisms underlying human TA that may bring new possibilities for future prevention and treatment
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