48 research outputs found
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Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia.
Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition
Cementomimetics—constructing a cementum-like biomineralized microlayer via amelogenin-derived peptides
This is the published version. Copyright 2012 Nature Publishing GroupCementum is the outer-, mineralized-tissue covering the tooth root and an essential part of the system of periodontal tissue that anchors the tooth to the bone. Periodontal disease results from the destructive behavior of the host elicited by an infectious biofilm adhering to the tooth root and left untreated, may lead to tooth loss. We describe a novel protocol for identifying peptide sequences from native proteins with the potential to repair damaged dental tissues by controlling hydroxyapatite biomineralization. Using amelogenin as a case study and a bioinformatics scoring matrix, we identified regions within amelogenin that are shared with a set of hydroxyapatite-binding peptides (HABPs) previously selected by phage display. One 22-amino acid long peptide regions referred to as amelogenin-derived peptide 5 (ADP5) was shown to facilitate cell-free formation of a cementum-like hydroxyapatite mineral layer on demineralized human root dentin that, in turn, supported attachment of periodontal ligament cells in vitro. Our findings have several implications in peptide-assisted mineral formation that mimic biomineralization. By further elaborating the mechanism for protein control over the biomineral formed, we afford new insights into the evolution of protein–mineral interactions. By exploiting small peptide domains of native proteins, our understanding of structure–function relationships of biomineralizing proteins can be extended and these peptides can be utilized to engineer mineral formation. Finally, the cementomimetic layer formed by ADP5 has the potential clinical application to repair diseased root surfaces so as to promote the regeneration of periodontal tissues and thereby reduce the morbidity associated with tooth loss
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Posterior vitreous detachment and retinal tear - a prospective study of community referrals.
Funder: University of Cambridge Retinal Research FundBACKGROUND: Retinal tears (RT) from posterior vitreous detachment (PVD) are an important and treatable cause of rhegmatogenous retinal detachment (RRD). Better understanding of the risk of RT from PVD will help plan urgent eye care. METHODS: Prospective observational case series over two years. Patients presenting to their optometrist, family doctor or emergency department with flashes and floaters were directed to a research clinic. History and examination, including slit-lamp biomicroscopy (SLB) and indentation indirect ophthalmoscopy (IIO), were performed by a single investigator, with two month follow-up for patients with confirmed PVD. Main outcome measures were incidence of PVD, RT, and RRD. RESULTS: 1010 patients were recruited. 896 (89%) patients had PVD at first assessment, of which 89 (8.8% of total cohort, 9.9% of PVD eyes) had RT and 8 had RRD. 21 (3%) of the remaining PVD patients developed RT in the subsequent two months and a further 9 (11%) patients with RT at initial assessment developed further tears by two months. 7 (0.7%) had asymptomatic RT in the fellow eye. 15% of RT were only visible on IIO and not SLB. Weiss ring was absent in 32% of eyes with RT. Patients with RT or RRD were more likely than 'PVD-only' eyes to have blurred or missing vision (p < 0.001), have higher rate of blue-green cataracts (p < 0.001), and longer axial lengths (p < 0.05). CONCLUSIONS AND RELEVANCE: This large, prospective study demonstrates a 9.9% rate of RT or RRD at the time of PVD, and emphasises the importance of IIO examination