Molecular Consequences of a Frameshifted DLX3 Mutant Leading to Tricho-Dento-Osseous Syndrome

Duverger, Olivier; Lee, Delia; Hassan, Mohammad Q.; Chen, Susie X.; Jaisser, Frédéric; Lian, Jane B.; Morasso, María I.

doi:10.1074/jbc.m709562200

Cited by 43 publications

(35 citation statements)

References 31 publications

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“…Disease has been postulated to result from haploinsufficiency (Nieminen et al, 2011) but other effects, including dominant negative through binding to WT DLX3 (Duverger et al, 2008), as well as gain of function, through interactions of the mutant protein with other transcription factors, have not been ruled out.…”

Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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Amelogenesis imperfecta (AI) is the name given to a heterogeneous group of conditions characterized by inherited developmental enamel defects. AI enamel is abnormally thin, soft, fragile, pitted and/or badly discolored, with poor function and aesthetics, causing patients problems such as early tooth loss, severe embarrassment, eating difficulties, and pain. It was first described separately from diseases of dentine nearly 80 years ago, but the underlying genetic and mechanistic basis of the condition is only now coming to light. Mutations in the gene AMELX, encoding an extracellular matrix protein secreted by ameloblasts during enamel formation, were first identified as a cause of AI in 1991. Since then, mutations in at least eighteen genes have been shown to cause AI presenting in isolation of other health problems, with many more implicated in syndromic AI. Some of the encoded proteins have well documented roles in amelogenesis, acting as enamel matrix proteins or the proteases that degrade them, cell adhesion molecules or regulators of calcium homeostasis. However, for others, function is less clear and further research is needed to understand the pathways and processes essential for the development of healthy enamel. Here, we review the genes and mutations underlying AI presenting in isolation of other health problems, the proteins they encode and knowledge of their roles in amelogenesis, combining evidence from human phenotypes, inheritance patterns, mouse models, and in vitro studies. An LOVD resource (http://dna2.leeds.ac.uk/LOVD/) containing all published gene mutations for AI presenting in isolation of other health problems is described. We use this resource to identify trends in the genes and mutations reported to cause AI in the 270 families for which molecular diagnoses have been reported by 23rd May 2017. Finally we discuss the potential value of the translation of AI genetics to clinical care with improved patient pathways and speculate on the possibility of novel treatments and prevention strategies for AI.

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Section: The Genetics Of Amelogenesis Imperfectamentioning

confidence: 99%

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

et al. 2017

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“…Another target gene of p63 that has been linked to a developmental disorder is Dlx3, mutations in which cause Tricho-Dento-Osseus (TDO) syndrome (Radoja et al , 2007;Price et al , 1998). In TDO syndrome, the mutant Dlx3 proteins have a dominant-negative function towards the wild type Dlx3 proteins, thus impairing the function of Dlx3 (Duverger et al , 2008). Interestingly, although p63 induces Dlx3 expression in basal keratinocytes, Dlx3 degrades p63 in suprabasal cell layers, suggesting that these proteins participate in an intricate feedback loop (Di Costanzo et al , 2009).…”

Section: P63 In Developmental Disordersmentioning

confidence: 99%

p63 in Skin Development and Ectodermal Dysplasias

Koster

2010

Journal of Investigative Dermatology

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The transcription factor p63 is critically important for skin development and maintenance. Processes that require p63 include epidermal lineage commitment, epidermal differentiation, cell adhesion, and basement membrane formation. Not surprisingly, alterations in the p63 pathway underlie a subset of ectodermal dysplasias, developmental syndromes in which the skin and skin appendages do not develop normally. This review summarizes the current understanding of the role of p63 in normal development and ectodermal dysplasias.

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“…Dlx3 is a member of the distalless homeobox family that interacts with transcription factors specific to mineralized tissue to regulate craniofacial and postnatal skeletal development (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Our results indicate that there is a cellular requirement for miR-665 to fine-tune the expression of Dlx3 within physiologic limits for maturation of progenitors to odontoblasts.…”

Section: Discussionmentioning

confidence: 75%

“…Mutations in DLX3 in humans have been associated with tricho-dento-osseous syndrome (TDO; OMIM 190320) and amelogenesis imperfecta with taurodontism (AIHHT; OMIM 104510), both of which are conditions characterized by abnormalities in tooth formation (35)(36)(37)(38)(39). During development, Dlx3 expression occurs in cranial neural crest cells, endochondral osteoblasts, odontoblasts, ameloblasts, hypertrophic chondrocytes, and the developing limb (40,41), and Dlx3-knockout mice die from placental failure at embryonic day 9.5 (E9.5), prior to bone and tooth formation (28).…”

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confidence: 99%

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

Heair

Kemper

Roy

et al. 2015

Molecular and Cellular Biology

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bStudies of proteins involved in microRNA (miRNA) processing, maturation, and silencing have indicated the importance of miRNAs in skeletogenesis, but the specific miRNAs involved in this process are incompletely defined. Here, we identified miRNA 665 (miR-665) as a potential repressor of odontoblast maturation. Studies with cultured cell lines and primary embryonic cells showed that miR-665 represses the expression of early and late odontoblast marker genes and stage-specific proteases involved in dentin maturation. Notably, miR-665 directly targeted Dlx3 mRNA and decreased Dlx3 expression. Furthermore, RNA-induced silencing complex (RISC) immunoprecipitation and biotin-labeled miR-665 pulldown studies identified Kat6a as another potential target of miR-665. KAT6A interacted physically and functionally with RUNX2, activating tissue-specific promoter activity and prompting odontoblast differentiation. Overexpression of miR-665 reduced the recruitment of KAT6A to Dspp and Dmp1 promoters and prevented KAT6A-induced chromatin remodeling, repressing gene transcription. Taken together, our results provide novel molecular evidence that miR-665 functions in an miRNA-epigenetic regulatory network to control dentinogenesis. D entinogenesis is the process by which dentin, the major mineralized tissue of teeth, is formed through progressive cytodifferentiation of progenitor cells to mature odontoblasts (1). Multiple layers of gene regulation, including those by microRNA (miRNA), orchestrate the physiologic process of dentinogenesis in a stage-specific manner (2). Progenitor cells, including dental papilla cells or dental follicle cells, derived from the ectomesenchyme of the cranial neural crest, differentiate into preodontoblasts and produce predentin. Predentin stimulates further differentiation of the cells it surrounds, giving rise to mature odontoblasts that produce dentin. Odontoblast secretion of dentin extracellular matrix proteins, including dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1), aids in the process of mineralization that forms primary dentin. However, the mechanisms of odontoblast-specific gene regulation by miRNA during dentinogenesis are not clearly understood.miRNAs are endogenous, noncoding RNAs implicated in posttranscriptional RNA silencing (3-9). The importance of miRNAs in skeletogenesis has been shown in mice by loss-offunction analysis of proteins involved in miRNA processing (Drosha and DGCR8), maturation (Dicer), and silencing (argonaute 2; AGO2), which revealed embryonic lethality and severe developmental defects upon loss of these proteins (10-15). Furthermore, cartilage-specific deletion of Dicer led to accelerated differentiation and subsequent cell death (11), whereas osteoblast-and osteoclast-specific deletion increased bone mass (13,16). Current studies on miRNA regulation of gene expression indicate a key role for this process in tooth development (17)(18)(19)(20) and in controlling cellular signaling (18,(21)(22)(23)(24)(25) and differentiation (2,26). However, ...

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Molecular Consequences of a Frameshifted DLX3 Mutant Leading to Tricho-Dento-Osseous Syndrome

Abstract: The homeodomain protein Distal-less-3 (Dlx3) plays a crucial role during embryonic development. This transcription factor is known to be essential for placental formation and to be involved in skin and skeletal organogenesis. In humans, a frameshift mutation in the coding sequence of the

Cited by 43 publications

References 31 publications

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

p63 in Skin Development and Ectodermal Dysplasias

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

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