DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism

Dong, Juan; Amor, David J.; Aldred, Michael J.; Gu, Tingting; Escamilla, Michael; MacDougall, Mary

doi:10.1002/ajmg.a.30521

Cited by 129 publications

(100 citation statements)

References 20 publications

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“…Furthermore, the direction and number of dental roots are different in the upper and lower molars; these properties together represent an important anatomical feature supporting the functions performed by human dentition. In humans, certain genetic mutations have been linked to root development defects (Dong et al, 2005;Yang et al, 2015). However, the majority of root defects observed in humans are associated with complex genetic disorders that lead to multiple developmental defects (reviewed by Luder, 2015).…”

Section: Root Developmental Defects In Humansmentioning

confidence: 99%

“…Taurodontism may have a genetic component; for example, in tricho-dento-osseous syndrome, which is associated with DLX3 mutations (Wright et al, 2008). Mutations in DLX3 are also associated with amelogenesis imperfecta hypoplastichypomaturation with taurodontism in humans (Dong et al, 2005). Of note, the ablation of Smad4, Nfic or Wnt10a in mice leads to similar phenotypes Liu et al, 2015;Yang et al, 2015).…”

Section: Root Developmental Defects In Humansmentioning

confidence: 99%

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Cellular and molecular mechanisms of tooth root development

2017

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The tooth root is an integral, functionally important part of our dentition. The formation of a functional root depends on epithelialmesenchymal interactions and integration of the root with the jaw bone, blood supply and nerve innervations. The root development process therefore offers an attractive model for investigating organogenesis. Understanding how roots develop and how they can be bioengineered is also of great interest in the field of regenerative medicine. Here, we discuss recent advances in understanding the cellular and molecular mechanisms underlying tooth root formation. We review the function of cellular structure and components such as Hertwig's epithelial root sheath, cranial neural crest cells and stem cells residing in developing and adult teeth. We also highlight how complex signaling networks together with multiple transcription factors mediate tissue-tissue interactions that guide root development. Finally, we discuss the possible role of stem cells in establishing the crown-to-root transition, and provide an overview of root malformations and diseases in humans.

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Section: Root Developmental Defects In Humansmentioning

confidence: 99%

Section: Root Developmental Defects In Humansmentioning

confidence: 99%

Cellular and molecular mechanisms of tooth root development

2017

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“…(Merlo et al 2002;Robledo et al 2002;Depew and Rubenstein, unpublished), and significantly one form of human ectrodactyly maps to the region of the Dlx5/6 locus (Crackower et al 1996). Additionally, Dlx3 mutations are now implicated in dental and osseous defects in patients with autosomal dominant amelogenesis imperfecta with taurodontism (Dong et al 2005) and tricho-dento-osseous syndrome (Haldeman et al 2004). …”

Section: Implications Of the DLX Mutants For Human Developmental Disomentioning

confidence: 99%

Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development

et al. 2005

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The branchial arches are meristic vertebrate structures, being metameric both between each other within the rostrocaudal series along the ventrocephalic surface of the embryonic head and within each individual arch: thus, just as each branchial arch must acquire a unique identity along the rostrocaudal axis, each structure within the proximodistal axis of an arch must also acquire a unique identity. It is believed that regional specification of metameric structures is controlled by the nested expression of related genes resulting in a regional code, a principal that is though to be demonstrated by the regulation of rostrocaudal axis development in animals exerted by the nested HOM-C/Hox homeobox genes. The nested expression pattern of the Dlx genes within the murine branchial arch ectomesenchyme has more recently led to the proposal of a Dlx code for the regional specification along the proximodistal axis of the branchial arches (i.e. it establishes intra-arch identity). This review re-examines this hypothesis, and presents new work on an allelic series of Dlx loss-of-function mouse mutants that includes various combinations of Dlx1, Dlx2, Dlx3, Dlx5 and Dlx6. Although we confirm fundamental aspects of the hypothesis, we further report a number of novel findings. First, contrary to initial reports, Dlx1, Dlx2 and Dlx1/2 heterozygotes exhibit alterations of branchial arch structures and Dlx2 -/-and Dlx1/2 -/-mutants have slight alterations of structures derived from the distal portions of their branchial arches. Second, we present evidence for a role for murine Dlx3 in the development of the branchial arches.Third, analysis of compound Dlx mutants reveals four grades of mandibular arch transformations and that the genetic interactions of cis first-order (e.g. Dlx5 and Dlx6 ), trans second-order (e.g. Dlx5 and Dlx2) and trans third-order paralogues (e.g. Dlx5 and Dlx1) result in significant and distinct morphological differences in mandibular arch development.We conclude by integrating functions of the Dlx genes within the context of a hypothesized general mechanism for the establishment of pattern and polarity in the first branchial arch of gnathostomes that includes regionally secreted growth factors such as Fgf8 and Bmp and other transcription factors such as Msx1, and is consistent both with the structure of the conserved gnathostome jaw bauplan and the elaboration of this bauplan to meet organismal end-point designs.

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“…The defect in Dlx3 leading to tricho-dento osseous syndrome appears to be associated with a four-nucleotide deletion just downstream of the homeodomain, resulting in a premature truncation of the protein. Amelogenesis imperfecta with taurodontism has similar characteristics as tricho-dento osseous syndrome and has also been associated with mutations with Dlx3 in some families investigated, albeit distinct from the fournucleotide deletion/mutation described above (7). Amelogenesis imperfecta is an autosomal dominant trait leading to dental enamel defects and enlarged pulp chambers and has been associated with a two-nucleotide deletion within the homeodomain of Dlx3.…”

mentioning

confidence: 93%

Smad6 Represses Dlx3 Transcriptional Activity through Inhibition of DNA Binding

Berghorn¹,

Clark-Campbell²,

Han³

et al. 2006

Journal of Biological Chemistry

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Dlx3 (Distal-less 3) is a homeobox-containing transcription factor required for normal placental development in mice. Here we demonstrate that Dlx3 interacts with Smad6, a member of a larger family of transcriptional regulators generally thought to regulate transforming growth factor ␤/bone morphogenetic protein signaling. Immunocytochemical and immunoprecipitation studies demonstrate overlapping nuclear localization and physical interaction between Dlx3 and Smad6 in human choriocarcinoma cells and in differentiated trophoblasts from human placenta. In vitro protein interaction studies mapped the Smad6 interaction domain within Dlx3 to residues 80 -163, a region of Dlx3 that includes a portion of the homeodomain. Dlx3 and Dlx4 share homology within this region, and Dlx4 was also found to bind Smad6. Using the Esx1 gene promoter as a model for a Dlx3-responsive gene, studies demonstrate two near consensus Dlx3 binding sites within the proximal 2.3 kb of the transcription start site. Interestingly, binding of Dlx3 to one of these two sites was inhibited by interaction with Smad6. Consistent with this result, expression of an Esx1 promoter luciferase reporter was increased by overexpression of Dlx3; this effect was reversed with co-expression of Smad6. Further, small interference RNAmediated knockdown of endogenous Smad6 increased Dlx3-dependent expression of the Esx1 gene promoter. Thus, Smad6 appears to functionally interact with Dlx3, altering the ability of Dlx3 to bind target gene promoters. Smad6 appears to play a modulatory role in the regulation of Dlx3-dependent gene transcription within placental trophoblasts.

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DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism

Cited by 129 publications

References 20 publications

Cellular and molecular mechanisms of tooth root development

Cellular and molecular mechanisms of tooth root development

Reassessing the Dlx code: the genetic regulation of branchial arch skeletal pattern and development

Smad6 Represses Dlx3 Transcriptional Activity through Inhibition of DNA Binding

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