Amelogenesis imperfecta caused by N-terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress

Brookes, Steven J.; Barron, Martin J.; Smith, Claire E. L.; Poulter, James A.; Mighell, Alan J.; Inglehearn, Chris F.; Brown, Catriona J.; Rodd, Helen; Kirkham, Jennifer; Dixon, Michael J.

doi:10.1093/hmg/ddx090

Cited by 20 publications

(25 citation statements)

References 49 publications

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“…These include ENAM c.92T>G, p.(L31R) (Brookes et al, 2017) and KLK4 c.632delT, p.(L211Rfs * 37) (Smith et al, 2017a). Some genes, for example FAM83H and WDR72 , show clear trends in the types and positions of AI-causing variants reported, giving clues as to how these variants cause disease.…”

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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“… Scanning electron micrographs of transverse sections through mandibular incisors of (A) WT mice, (B) mice heterozygous for the Amelx p.Y64H mutation and (C) mice heterozygous for the Enam p.S55I mutation at or near the point of eruption (previously reported by Brookes et al, 2014 , 2017 ). (A) The incremental secretion of the inner enamel (in the direction indicated by arrow 1) by WT ameloblasts produces the decussating prismatic architecture characteristic of rodent enamel.…”

Section: Er Stress and The Upr As An Etiological Factor In Aimentioning

confidence: 88%

“…The first evidence that ER stress could drive AI came from detailed phenotyping of a mouse model exhibiting an Amelx p.(Y64H) mutation (Barron et al, 2010 ; Brookes et al, 2014 ). More recently mouse Enam p.(S55I) and human ENAM p.(L31R) mutations have also been associated with ameloblast ER stress (Brookes et al, 2017 ). ENAM is expressed at very low levels compared to AMELX and is biochemically distinct—in mice being over seven times the molecular weight of AMELX and more basic in nature (Hu et al, 1998 ).…”

Section: Er Stress and The Upr As An Etiological Factor In Aimentioning

confidence: 99%

“…Incisor enamel from heterozygous mice of both genotypes revealed an unusual phenotype in which the first 30–50 μm of initially secreted incisor enamel (i.e., the inner enamel adjacent to the dentine) exhibited the decussating prismatic structure characteristic of WT rodent incisor enamel but this was overlaid with subsequently secreted, structurally abnormal, aprismatic enamel (Brookes et al, 2014 , 2017 ). This shared structural phenotype suggests a common underlying etiology despite the presumed functional differences between AMELX and ENAM.…”

Section: Er Stress and The Upr As An Etiological Factor In Aimentioning

confidence: 99%

“…The dotted line marks demarcation between the inner decussating and outer non-decussating enamel. (B,C) were derived under Creative Commons CC BY licenses 3.0 and 4.0 ( https://creativecommons.org/licenses/ ) respectively from: Brookes et al ( 2014 ), and phenotypic rescue using 4-phenylbutyrate; and Brookes et al ( 2017 ). Both published by Oxford University press.…”

Section: Er Stress and The Upr As An Etiological Factor In Aimentioning

confidence: 99%

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The Unfolded Protein Response in Amelogenesis and Enamel Pathologies

et al. 2017

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During the secretory phase of their life-cycle, ameloblasts are highly specialized secretory cells whose role is to elaborate an extracellular matrix that ultimately confers both form and function to dental enamel, the most highly mineralized of all mammalian tissues. In common with many other “professional” secretory cells, ameloblasts employ the unfolded protein response (UPR) to help them cope with the large secretory cargo of extracellular matrix proteins transiting their ER (endoplasmic reticulum)/Golgi complex and so minimize ER stress. However, the UPR is a double-edged sword, and, in cases where ER stress is severe and prolonged, the UPR switches from pro-survival to pro-apoptotic mode. The purpose of this review is to consider the role of the ameloblast UPR in the biology and pathology of amelogenesis; specifically in respect of amelogenesis imperfecta (AI) and fluorosis. Some forms of AI appear to correspond to classic proteopathies, where pathological intra-cellular accumulations of protein tip the UPR toward apoptosis. Fluorosis also involves the UPR and, while not of itself a classic proteopathic disease, shares some common elements through the involvement of the UPR. The possibility of therapeutic intervention by pharmacological modulation of the UPR in AI and fluorosis is also discussed.

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An endoplasmic reticulum stress regulator, Tmbim6, modulates secretory stage of mice molar

Aryal

Neupane

Adhikari

et al. 2019

Journal Cellular Physiology

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To understand the role of endoplasmic reticulum (ER)-stress in mice molar development, we studied Tmbim6 that antagonizes the unfolded protein response, using Tmbim6 knockout (KO) mice and in vitro organ cultivation with knocking down using small interfering RNA. During molar development, Tmbim6 is expressed in developing tooth at E14-E16, postnatal0 (PN0), and PN6. Mineral content in Tmbim6 KO enamel was reduced while dentin was slightly increased revealing ultrastructural changes in pattern formation of both enamel and dentin. Moreover, odontoblast differentiation was altered with increased Dspp expression at PN0 followed by altered AMELX localizations at PN5. These results were confirmed by in vitro organ cultivation and showed altered Bmp signaling, proliferation, and actin rearrangement in the presumptive ameloblast and odontoblasts that followed the altered expression of differentiation and ER stress-related signaling molecules at E16.5. Overall, ER stress modulated by Tmbim6 would play important roles in patterned dental hard tissue formation in mice molar within a limited period of development. K E Y W O R D Samelogenesis, dentinogenesis, ER stress, molar development, Tmbim6 knockout

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Amelogenesis imperfecta caused by N-terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress

Cited by 20 publications

References 49 publications

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

Amelogenesis Imperfecta; Genes, Proteins, and Pathways

The Unfolded Protein Response in Amelogenesis and Enamel Pathologies

An endoplasmic reticulum stress regulator, Tmbim6, modulates secretory stage of mice molar

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