Phenotype and Variant Spectrum in the<i>LAMB3</i>Form of Amelogenesis Imperfecta

Smith, Claire E. L.; Poulter, James A.; Brookes, Steven J.; Murillo, Gina; Silva, S; Brown, Catriona J.; Patel, Anesha; Hussain, Hafiz Muhammad Jafar; Kirkham, Jennifer; Inglehearn, Chris F.; Mighell, Alan J.

doi:10.1177/0022034519835205

Cited by 19 publications

(27 citation statements)

References 32 publications

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“…Early enamel attrition after eruption is probably a consequence of abnormal enamel structure even though enamel prisms are present. The disorganised, non‐prismatic layers of enamel noted in Figure and Figure S5 resemble closely the enamel architecture in AI patients carrying heterozygous LAMB3 variants, as reported by Smith et al AI‐causing variants in LAMB3 and other hemidesmosomal proteins are thought to result in defective attachment of ameloblasts to the enamel matrix. Teeth from families with AI due to either LAMB3 or RELT variants have layers of disorganised, non‐prismatic enamel lamellae and areas where enamel is prismatic but abnormal.…”

Section: Discussionsupporting

confidence: 77%

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New missense variants in RELT causing hypomineralised amelogenesis imperfecta

et al. 2020

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Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non-syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix.Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT-variant associated AI. K E Y W O R D S amelogenesis imperfecta, enamel, RELT, tumour necrosis factor receptor

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Section: Discussionsupporting

confidence: 77%

“…Libraries were sequenced with a 150 bp paired‐end protocol on an Illumina Hi‐Seq 3000 sequencer. Sequences were aligned and variants filtered as described previously …”

Section: Methodsmentioning

confidence: 99%

New missense variants in RELT causing hypomineralised amelogenesis imperfecta

et al. 2020

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“…Mutations in LAMA3, LAMC2, COL17A1, ITGA6, and ITGB4 are associated with the blistering skin disorder junctional epidermolysis bullosa and cause severe enamel hypoplasia, grooves and enamel pitting (McGrath et al, 1996; Wright, 2006; Murrell et al, 2007; Almaani et al, 2009; Kim et al, 2013; Wang et al, 2015; Gostynska et al, 2016). Both LAMC2 and LAMA3 are a part of the laminin 332 complex (also called laminin 5), known to be involved in tooth bud differentiation and pre-secretory ameloblast activity, and previously seen observed with amelotin (AMTN) at the interface between ameloblasts and enamel during early and late maturation (Nanci et al, 1993; Yoshiba et al, 2002; Sawada, 2015; Smith et al, 2019). Because we observe LAMA3 at high abundance in secretory enamel, we speculate that this protein may play a role in enamel secretion, possibly related to 332 functions corresponding to cell anchorage, mobility, or signaling (Ryan et al, 1999).…”

Section: Discussionmentioning

confidence: 89%

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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“…Three micrograms of genomic DNA from a single individual from each family (marked with an arrow on the pedigrees shown in Figure 1) were subjected to WES and analyzed as described previously (C. E. L. Smith et al, 2019). Variants present in the dbSNP150 database of NCBI or the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org) with a minor allele frequency ≥1% were excluded.…”

Section: Whole-exome Sequencing (Wes) and Analysismentioning

confidence: 99%

Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20

et al. 2021

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Amelogenesis imperfecta (AI) describes a heterogeneous group of developmental enamel defects that typically have Mendelian inheritance. Exome sequencing of 10 families with recessive hypomaturation AI revealed four novel and one known variants in the matrix metallopeptidase 20 (MMP20) gene that were predicted to be pathogenic. MMP20 encodes a protease that cleaves the developing extracellular enamel matrix and is necessary for normal enamel crystal growth during amelogenesis. New homozygous missense changes were shared between four families of Pakistani heritage (c.625G>C; p.(Glu209Gln)) and two of Omani origin (c.710C>A; p.(Ser237Tyr)). In two families of UK This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Phenotype and Variant Spectrum in theLAMB3Form of Amelogenesis Imperfecta

Cited by 19 publications

References 32 publications

New missense variants in RELT causing hypomineralised amelogenesis imperfecta

New missense variants in RELT causing hypomineralised amelogenesis imperfecta

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

Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20

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