&lt;i&gt;DLX3 &lt;/i&gt;Homeodomain Mutations Cause Tricho-Dento-Osseous Syndrome with Novel Phenotypes

Nieminen, Pekka; Lukinmaa, Pirjo‐Liisa; Alapulli, Heikki; Methuen, Mirja; Suojärvi, Timo; Kivirikko, Sirpa; Peltola, J.; Asikainen, Mikko; Alaluusua, Satu

doi:10.1159/000322561

Cited by 49 publications

(52 citation statements)

References 63 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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“…Thus far, five mutations in DLX3 have been associated with TDO syndrome, all of which have an autosomal dominant mode of inheritance. The clinical observations associated with the different mutations in DLX3 reported so far are associated with highly penetrant tooth defects, and with more variable defects in hair and bone (1)(2)(3)(4)(5)(6). Furthermore, dental defects are the most debilitating trait of TDO patients who are highly susceptible to infections and abscesses.…”

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confidence: 99%

“…In humans, mutations in the DLX3 homeodomain transcription factor gene are associated with Tricho-Dento-Osseous (TDO) 3 syndrome, an ectodermal dysplasia characterized by mutation-dependent defects in hair (kinky hair), teeth (enamel hypoplasia and taurodontism), and bone (increased bone density in the cranium and long bones) development (1,2). Thus far, five mutations in DLX3 have been associated with TDO syndrome, all of which have an autosomal dominant mode of inheritance.…”

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confidence: 99%

Neural Crest Deletion of Dlx3 Leads to Major Dentin Defects through Down-regulation of Dspp

Duverger

Zah

Isaac

et al. 2012

Journal of Biological Chemistry

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Background: Mutations of DLX3 in humans lead to tooth defects, but normal Dlx3 function in tooth is unknown. Results: Mice lacking Dlx3 in the dental mesenchyme exhibit major dentin defects, and Dspp is a direct target of Dlx3 in odontoblasts. Conclusion: Dspp, a major component of dentin matrix, is directly regulated by Dlx3 in odontoblasts. Significance: Dspp is the first direct target of Dlx3 identified in odontoblasts.

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“…Mutations of DLX3 are closely related to Tricho-Dento-Osseous syndrome (TDO; OMIM 190320), which is a disorder with autosomal dominant inheritance mainly characterized by kinky hair, thin-pitted enamel (with remarkable attrition), dentin hypoplasia, and taurodontism as well as increased thickness and density of cranial and mandibular bones. To date, only six mutations in the DLX3 gene have been identified within minority family groups78910 (Supplementary Fig. S1).…”

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confidence: 99%

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

Zhao

Han

Liu

et al. 2016

Sci Rep

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The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation.

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<i>DLX3 </i>Homeodomain Mutations Cause Tricho-Dento-Osseous Syndrome with Novel Phenotypes

Cited by 49 publications

References 63 publications

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Neural Crest Deletion of Dlx3 Leads to Major Dentin Defects through Down-regulation of Dspp

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

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