Validation of Amelogenesis Imperfecta Inferred from Amelogenin Evolution

Delgado, Sidney; Ishiyama, Mikio; Sire, Jean‐Yves

doi:10.1177/154405910708600405

Cited by 28 publications

(29 citation statements)

References 30 publications

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“…This also reveals that the protein needs to be highly structured on its full-length for a correct function of the enzyme. This high selective pressure along the whole sequence length contrasts with the low constraints observed in unstructured (disordered) proteins previously studied: AMELX (40% of sensitive positions (27)), ENAM (7% (28)), MEPE (14% (29)), AMTN (8% (30)), DMP1 (20% (31)), and AMBN (18%). 7 This corroborates the crucial importance of TNSALP in mammals and its involvement in various functional, but also structural, roles, not yet exhaustively identified.…”

Section: Discussionmentioning

confidence: 59%

“…Recently, our group successfully used this approach for predicting sensitive positions in various proteins of the secretory calcium-binding phosphoprotein family (26), and showed that missense mutations lead to genetic diseases. This approach was demonstrated on the following proteins: amelogenin (27), enamelin (28), matrix extracellular phospho-glycoprotein (29), amelotin (30), dentin matrix protein 1 (31), and ameloblastin. 6 Here, we perform the evolutionary molecular analysis of mammalian TNSALP to (i) highlight the functional or structural importance of various positions and domains; (ii) predict sensitive positions that should be responsible for a genetic disorder when substituted; and (iii) validate our predictions by using missense mutations reported in humans.…”

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confidence: 99%

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Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

Silvent

Gasse

Mornet

et al. 2014

Journal of Biological Chemistry

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Background:We used evolutionary analysis of alkaline phosphatase (tissue nonspecific alkaline phosphatase, TNSALP) to predict missense mutations leading to hypophosphatasia. Results: We found 469 sensitive positions and validated 99% of the 204 known mutations. Conclusion: It is a more powerful method than in silico models to validate missense mutations in TNSALP. Significance: Such an approach should be widely used to support genetic diagnostics.

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Section: Discussionmentioning

confidence: 59%

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confidence: 99%

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

Silvent

Gasse

Mornet

et al. 2014

Journal of Biological Chemistry

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“…This review will focus on the effects of human amelogenin gene mutations, and on animal models generated to reproduce the human AI genotype and phenotype. Similarities between human and murine amelogenin genes are apparent at the levels of gene structure, DNA sequence and pattern of expression during development 19 .…”

Section: Gene Mutations Lead To Amelogenesis Imperfecta (Ai) In Humansmentioning

confidence: 99%

The Amelogenin Proteins and Enamel Development in Humans and Mice

Gibson

2011

Journal of Oral Biosciences

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Before a tooth erupts into the oral cavity, the mineralized enamel and dentin layers begin to develop. During these early stages of enamel formation, an abundant group of proteins known as amelogenins are secreted by ameloblast cells within the developing tooth. These proteins are required for the enamel layer to reach its normal thickness and attain its intricate structure. Human patients with amelogenin gene mutations have a condition referred to as amelogenesis imperfecta, and we have analyzed human gene defects so that we can recreate them in mice. We have generated mice with a null amelogenin mutation where no amelogenin is produced, mice that over-express normal and mutated amelogenins, and over-expressors have been mated to null mice for rescue experiments. Because there are at least 15 messages that are alternatively spliced from a single amelogenin primary RNA transcript, these approaches have begun to reveal the functions of individual amelogenin proteins during enamel development. Finally, amelogenins are processed by carefully regulated proteolytic digestion leading to many additional amelogenin peptides and it is likely that protein function is altered during this developmental process. We have also had some surprises, as one of our mouse models develops odontogenic tumors, and we know now that some of the amelogenins are expressed in other regions of the body outside of the oral cavity, and may have a role in signal transduction.

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“…The abundant, highly conserved amelogenins are expressed from the X-chromosomal amelogenin gene in mice [Chapman et al, 1991;Delgado et al, 2007]. The primary RNA transcript can be alternatively spliced to form at least 15 mRNAs [Hu et al, 1997;Li et al, 1998Li et al, , 2006, which are translated into amelogenin proteins that vary in abundance.…”

Section: Introductionmentioning

confidence: 99%

The Leucine-Rich Amelogenin Peptide Alters the Amelogenin Null Enamel Phenotype

Gibson

Daly³

et al. 2008

Cells Tissues Organs

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Introduction: The amelogenin proteins secreted by ameloblasts during dental enamel development are required for normal enamel structure. Amelx null (KO) mice have hypoplastic, disorganized enamel similar to that of human patients with mutations in the AMELX gene, and provide a model system for studies of the enamel defect amelogenesis imperfecta. Because many amelogenin proteins are present in developing enamel due to RNA alternative splicing and proteolytic processing, understanding the function of individual amelogenins has been challenging. Purpose: Our objective was to better understand the role of LRAP, a 59 amino acid leucine-rich amelogenin peptide, in the development of enamel. Approach: Teeth from transgenic mice that express LRAP under control of the Amelx regulatory regions were analyzed for mechanical properties, and transgenic males were mated with female KO mice. Male offspring with a null background that were transgene positive or transgene negative were compared to determine phenotypic differences using microcomputed tomography (microCT) and scanning electron microscopy (SEM). Results: Nanoindentation revealed no differences between LRAP transgenic and wild-type murine enamel. Using microCT, LRAPKO enamel volume and density measurements were similar to those from KO mice. However, in etched samples examined by SEM, the organization of the enamel rod pattern was altered by the presence of the LRAP transgene. Conclusions: The presence of LRAP leads to changes in enamel appearance compared to enamel from KO mice. Expression of a combination of amelogenin transgenes in KO mice may lead to rescue of the individual characteristics of normal enamel.

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Validation of Amelogenesis Imperfecta Inferred from Amelogenin Evolution

Cited by 28 publications

References 30 publications

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

Molecular Evolution of the Tissue-nonspecific Alkaline Phosphatase Allows Prediction and Validation of Missense Mutations Responsible for Hypophosphatasia

The Amelogenin Proteins and Enamel Development in Humans and Mice

The Leucine-Rich Amelogenin Peptide Alters the Amelogenin Null Enamel Phenotype

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