Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta

Smith, Claire E. L.; Whitehouse, Laura Le.; Poulter, James A.; Brookes, Steven J.; Day, Peter; Soldani, Francesca; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

doi:10.1038/ejhg.2017.79

Cited by 19 publications

(27 citation statements)

References 13 publications

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“…rs7011390866,304,32912.962.6343.48E-060.73421.3293.41E-05rs727879391626,556,88715.852.632.20E-07−4.1711.594 7.51E-11 HS3ST4 Heparan sulfate proteoglycans are coreceptors for FGFR22b, whose signaling is essential for progenitor survival and proliferation in several organs, including the submandibular gland and the tooth [82]rs48018551951,348,572− 17.333.4593.24E-06− 0.41751.0052.66E-06 POLD1 Mutations cause Mandibular Hypoplasia, Deafness and Progeroid features (MDP) syndrome, a premature aging syndrome which results in severe dental crowding and irregular teeth [83]. ACPT Recessive mutations in ACPT cause hypoplastic amelogenesis imperfecta; ACPT supplies phosphate during dentine formation [84]. KLK1 Protein product is abundant in salivary proteome [85], and is involved in cellular inflammatory processes [86].…”

Section: Resultsmentioning

confidence: 99%

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Orlova¹,

Carlson

Lee

et al. 2019

BMC Oral Health

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Background Dental caries is the most common chronic disease in the US and disproportionately affects racial/ethnic minorities. Caries is heritable, and though genetic heterogeneity exists between ancestries for a substantial portion of loci associated with complex disease, a genome-wide association study (GWAS) of caries specifically in African Americans has not been performed previously. Methods We performed exploratory GWAS of dental caries in 109 African American adults (age > 18) and 96 children (age 3–12) from the Center for Oral Health Research in Appalachia (COHRA1 cohort). Caries phenotypes (DMFS, DMFT, dft, and dfs indices) assessed by dental exams were tested for association with 5 million genotyped or imputed single nucleotide polymorphisms (SNPs), separately in the two age groups. The GWAS was performed using linear regression with adjustment for age, sex, and two principal components of ancestry. A maximum of 1 million adaptive permutations were run to determine empirical significance. Results No loci met the threshold for genome-wide significance, though some of the strongest signals were near genes previously implicated in caries such as antimicrobial peptide DEFB1 (rs2515501; p = 4.54 × 10− 6) and TUFT1 (rs11805632; p = 5.15 × 10− 6). Effect estimates of lead SNPs at suggestive loci were compared between African Americans and Caucasians (adults N = 918; children N = 983). Significant (p < 5 × 10− 8) genetic heterogeneity for caries risk was found between racial groups for 50% of the suggestive loci in children, and 12–18% of the suggestive loci in adults. Conclusions The genetic heterogeneity results suggest that there may be differences in the contributions of genetic variants to caries across racial groups, and highlight the critical need for the inclusion of minorities in subsequent and larger genetic studies of caries in order to meet the goals of precision medicine and to reduce oral health disparities.

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Section: Resultsmentioning

confidence: 99%

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Orlova¹,

Carlson

Lee

et al. 2019

BMC Oral Health

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“…While ALPL abundance was low in surface enamel and has been reported previously, ACPT was detected in secretory and early maturation stage enamel, with high abundance in regions where we observe both phosphorylated and unphosphorylated P173+LRAP products (Figure 4A; Pandya et al, 2017). Notably, recent clinical data indicates that ACPT mutations can result in hypoplastic amelogenesis imperfecta (Seymen et al, 2016; Smith et al, 2017). The distributions of ACPT and unphosphorylated P173 plus LRAP in our enamel dataset suggest a potential ACPT-mediated dephosphorylation of AMELX, a hypothesis to be further tested experimentally.…”

Section: Discussionmentioning

confidence: 99%

Mapping the Tooth Enamel Proteome and Amelogenin Phosphorylation Onto Mineralizing Porcine Tooth Crowns

Green¹,

Schulte²,

Lee

et al. 2019

Front. Physiol.

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Tooth enamel forms in an ephemeral protein matrix where changes in protein abundance, composition and posttranslational modifications are critical to achieve healthy enamel properties. Amelogenin (AMELX) with its splice variants is the most abundant enamel matrix protein, with only one known phosphorylation site at serine 16 shown in vitro to be critical for regulating mineralization. The phosphorylated form of AMELX stabilizes amorphous calcium phosphate, while crystalline hydroxyapatite forms in the presence of the unphosphorylated protein. While AMELX regulates mineral transitions over space and time, it is unknown whether and when un-phosphorylated amelogenin occurs during enamel mineralization. This study aims to reveal the spatiotemporal distribution of the cleavage products of the most abundant AMLEX splice variants including the full length P173, the shorter leucine-rich amelogenin protein (LRAP), and the exon 4-containing P190 in forming enamel, all within the context of the changing enamel matrix proteome during mineralization. We microsampled permanent pig molars, capturing known stages of enamel formation from both crown surface and inner enamel. Nano-LC-MS/MS proteomic analyses after tryptic digestion rendered more than 500 unique protein identifications in enamel, dentin, and bone. We mapped collagens, keratins, and proteolytic enzymes (CTSL, MMP2, MMP10) and determined distributions of P173, LRAP, and P190 products, the enamel proteins enamelin (ENAM) and ameloblastin (AMBN), and matrix-metalloprotease-20 (MMP20) and kallikrein-4 (KLK4). All enamel proteins and KLK4 were near-exclusive to enamel and in excellent agreement with published abundance levels. Phosphorylated P173 and LRAP products decreased in abundance from recently deposited matrix toward older enamel, mirrored by increasing abundances of testicular acid phosphatase (ACPT). Our results showed that hierarchical clustering analysis of secretory enamel links closely matching distributions of unphosphorylated P173 and LRAP products with ACPT and non-traditional amelogenesis proteins, many associated with enamel defects. We report higher protein diversity than previously published and Gene Ontology (GO)-defined protein functions related to the regulation of mineral formation in secretory enamel (e.g., casein α-S1, CSN1S1), immune response in erupted enamel (e.g., peptidoglycan recognition protein, PGRP), and phosphorylation. This study presents a novel approach to characterize and study functional relationships through spatiotemporal mapping of the ephemeral extracellular matrix proteome.

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“…However, the function of ACP4 during amelogenesis is currently poorly understood. No mouse model has been characterized, but recent reports have described seven missense variants with autosomal recessive hypoplastic AI in humans (MIM #617297) (Seymen et al 2016 ; Smith et al 2017b ). Our results also indicate hypoplasticity of enamel as the principal feature of enamel associated with the loss of ACP4 function.…”

Section: Discussionmentioning

confidence: 99%

Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants

et al. 2019

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Amelogenesis imperfecta (AI) refers to a genetically and clinically heterogeneous group of inherited disorders affecting the structure, composition, and quantity of tooth enamel. Both non-syndromic and syndromic forms of AI have been described and several genes affecting various aspects of the enamel physiology have been reported. Genetically modified murine models of various genes have provided insights into the complex regulation of proper amelogenesis. Non-syndromic AI occurs spontaneously also in dogs with known recessive variants in ENAM and SLC24A4 genes. Unlike rodents with a reduced dentition and continuously erupting incisors, canine models are valuable for human AI due to similarity in the dental anatomy including deciduous and permanent teeth. We have performed a series of clinical and genetic analyses to investigate AI in several breeds of dogs and describe here two novel recessive variants in the ENAM and ACP4 genes. A fully segregating missense variant (c.716C>T) in exon 8 of ENAM substitutes a well-conserved proline to leucine, p.(Pro239Leu), resulting in a clinical hypomineralization of teeth. A 1-bp insertion in ACP4 (c.1189dupG) is predicted to lead to a frameshift, p.(Ala397Glyfs), resulting in an abnormal C-terminal part of the protein, and hypoplastic AI. The ENAM variant was specific for Parson Russell Terriers with a carrier frequency of 9%. The ACP4 variant was found in two breeds, Akita and American Akita with a carrier frequency of 22%. These genetic findings establish novel canine models of human AI with a particular interest in the case of the ACP4-deficient model, since ACP4 physiology is poorly characterized in human AI. The affected dogs could also serve as preclinical models for novel treatments while the breeds would benefit from genetic tests devised here for veterinary diagnostics and breeding programs. Electronic supplementary material The online version of this article (10.1007/s00439-019-01997-8) contains supplementary material, which is available to authorized users.

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Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta

Cited by 19 publications

References 13 publications

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Pilot GWAS of caries in African-Americans shows genetic heterogeneity

Mapping the Tooth Enamel Proteome and Amelogenin Phosphorylation Onto Mineralizing Porcine Tooth Crowns

Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants

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