Institute of Biomedical and Clinical Science

Plymouth, United Kingdom

Institute of Biomedical and Clinical Science

Plymouth, United Kingdom
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Richardson S.J.,University of Plymouth | Richardson S.J.,Institute of Biomedical and Clinical science | Willcox A.,University of Exeter | Bone A.J.,University of Brighton | And 2 more authors.
Seminars in Immunopathology | Year: 2011

Type 1 diabetes is a chronic autoimmune disease characterised by the selective destruction of pancreatic beta (β) cells. The understanding of the aetiology of this disease has increased dramatically in recent years by the study of tissue recovered from patients, from analysis of the responses of isolated islet and β-cells in tissue culture and via the use of animal models. However, knowledge of the immunopathology of type 1 diabetes in humans is still relatively deficient due largely to the difficulty of accessing appropriate samples. Here we review the state of current knowledge in relation to the histopathological features of the disease in humans. We focus specifically on recent-onset type 1 diabetes cases since in such patients, evidence of the ongoing disease process is still present. We chart the progression of the disease by describing the characteristic features of the pancreas, consider the sequence of immune cell infiltration and discuss the abnormalities of MHC antigen expression. The possibility that these changes might derive from a persistent enteroviral infection of the islet beta cells is examined. © 2010 Springer-Verlag.


Rubio-Cabezas O.,Institute of Biomedical and Clinical Science | Rubio-Cabezas O.,Hospital Infantil Universitario Nino Jesus | Rubio-Cabezas O.,CIBER ISCIII | Jensen J.N.,Hagedorn Research Institute | And 5 more authors.
Diabetes | Year: 2011

OBJECTIVE - NEUROG3 plays a central role in the development of both pancreatic islets and enteroendocrine cells. Homozygous hypomorphic missense mutations in NEUROG3 have been recently associated with a rare form of congenital malabsorptive diarrhea secondary to enteroendocrine cell dysgenesis. Interestingly, the patients did not develop neonatal diabetes but childhood-onset diabetes. We hypothesized that null mutations in NEUROG3 might be responsible for the disease in a patient with permanent neonatal diabetes and severe congenital malabsorptive diarrhea. RESEARCH DESIGN AND METHODS - The single coding exon of NEUROG3 was amplified and sequenced from genomic DNA. The mutant protein isoforms were functionally characterized by measuring their ability to bind to an E-box element in the NEUROD1 promoter in vitro and to induce ectopic endocrine cell formation and cell delamination after in ovo chicken endoderm electroporation. RESULTS - Two different heterozygous point mutations in NEUROG3 were identified in the proband [c.82>.T (p.E28X) and c.404T>C (p.L135P)], each being inherited from an unaffected parent. Both in vitro and in vivo functional studies indicated that the mutant isoforms are biologically inactive. In keeping with this, no enteroendocrine cells were detected in intestinal biopsy samples from the patient. CONCLUSIONS - Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans. © 2011 by the American Diabetes Association.


Christmas J.,University of Exeter | Keedwell E.,University of Exeter | Frayling T.M.,Institute of Biomedical and Clinical Science | Perry J.R.B.,Institute of Biomedical and Clinical Science
Information Sciences | Year: 2011

Around 1.8 million people in the UK have type 2 diabetes, representing about 90% of all diabetes cases in the UK. Genome wide association studies have recently implicated several new genes that are likely to be associated with this disease. However, common genetic variants so far identified only explain a small proportion of the heritability of type 2 diabetes. The interaction of two or more gene variants, may explain a further element of this heritability but full interaction analyses are currently highly computationally burdensome or infeasible. For this reason this study investigates an ant colony optimisation (ACO) approach for its ability to identify common gene variants associated with type 2 diabetes, including putative epistatic interactions. This study uses a dataset comprising 15,309 common (>5% minor allele frequency) SNPs from chromosome 16, genotyped in 1924 type 2 diabetes cases and 2938 controls. This chromosome contains two previously determined associations, one of which is replicated in additional samples. Although no epistatic interactions have been previously reported on this dataset, we demonstrate that ACO can be used to discover single SNP and plausible epistatic associations from this dataset and is shown to be both accurate and computationally tractable on large, real datasets of SNPs with no expert knowledge included in the algorithm. © 2011 Elsevier Inc. All rights reserved.


Harries L.W.,Institute of Biomedical and Clinical science
Biochemical Society Transactions | Year: 2012

The central dogma of molecular biology states that DNA is transcribed into RNA, which in turn is translated into proteins. We now know, however, that as much as 50% of the transcriptome has no protein-coding potential, but rather represents an important class of regulatory molecules responsible for the finetuning of gene expression. Although the role of small regulatory RNAs [microRNAs and siRNAs (small interfering RNA)] is well defined, another much less characterized category of non-coding transcripts exists, namely lncRNAs (long non-coding RNAs). Pervasively expressed by eukaryotic genomes, lncRNAs can be kilobases long and regulate their targets by influencing the epigenetic control, chromatin status, mRNA processing or translation capacity of their targets. In the present review, I outline the potential mechanisms of action of lncRNAs, the cellular processes that have been associated with them, and also explore some of the emerging evidence for their involvement in common human disease. ©The Authors Journal compilation ©2012 Biochemical Society.


Murphy R.,University of Auckland | Ibanez L.,University of Barcelona | Hattersley A.,Institute of Biomedical and Clinical science | Tost J.,French Atomic Energy Commission
BMC Medical Genetics | Year: 2012

Background: Insulin like growth factor 2 (IGF2) is an imprinted gene, which has an important role in fetal growth as established in mice models. IGF2 is downregulated through hypomethylation of a differentially methylated region (DMR) in Silver Russell syndrome (SRS), characterised by growth restriction. We have previously reported that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in a woman without body asymmetry or other SRS features resulted from a balanced translocation affecting the regulation of her IGF2 gene expression. We hypothesised that severe pre- and post-natal growth restriction associated with insulin resistance and precocious pubarche in the absence of SRS are also caused by downregulation of IGF2 through hypomethylation, gene mutation or structural chromosomal abnormalities.Methods: We performed routine karyotyping, IGF2 gene sequencing and investigated DNA methylation of the IGF2 differentially methylated region (DMR)0 and H19 DMR using pyrosequencing, in four women selected for very low birth weight (<-3 SDS for gestational age), precocious pubarche, short adult stature (<-2 SDS), and insulin resistance (defined as HOMA-IS < 80%); and compared their methylation results to those of 95 control subjects.Results: We identified a 20 year old woman with severe hypomethylation at both DMRs. She was the smallest at birth (birthweight SDS,-3.9), and had the shortest adult height (143 cm). The patient was diagnosed with polycystic ovarian syndrome at the age of 15 years, and had impaired fasting glucose in the presence of a low BMI (19.2 kg/m2).Conclusions: Our case of growth restriction, premature pubarche and insulin resistance in the absence of body asymmetry or other features of SRS adds to the expanding phenotype of IGF2/H19 methylation abnormalities. Further studies are needed to confirm whether growth restriction in association with premature pubarche and insulin resistance is a specific manifestation of reduced IGF2 expression. © 2012 Murphy et al.; licensee BioMed Central Ltd.


Frayling T.M.,Institute of Biomedical and Clinical Science
Clinical Medicine, Journal of the Royal College of Physicians of London | Year: 2014

Before 2007 the number of common genetic variants reproducibly associated with common diseases and traits was fewer than 20. There are now many hundreds of variants reliably associated with all types of diseases and traits, from male pattern baldness to height to common disease predisposition, including metabolic disease, autoimmune disease and germline predisposition to cancer. Despite this success at identifying variants, the GWAS findings are not generally clinically useful to individual patients. Instead they represent a first step towards improved understanding of disease aetiology. © Royal College of Physicians 2014. All rights reserved.


Todd A.G.,Institute of Biomedical and Clinical Science | Morse R.,Institute of Biomedical and Clinical Science | Shaw D.J.,Institute of Biomedical and Clinical Science | McGinley S.,Institute of Biomedical and Clinical Science | And 2 more authors.
Journal of Molecular Biology | Year: 2010

Childhood spinal muscular atrophy is caused by a reduced expression of the survival motor neuron (SMN) protein. SMN has been implicated in the axonal transport of β-actin mRNA in both primary and transformed neuronal cell lines, and loss of this function could account, at least in part, for spinal muscular atrophy onset and pathological specificity. Here we have utilised a targeted screen to identify mRNA associated with SMN, Gemin2 and Gemin3 in the cytoplasm of a human neuroblastoma cell line, SHSY5Y. Importantly, we have provided the first direct evidence that β-actin mRNA is present in SMN cytoplasmic complexes in SHSY5Y cells. © 2010 Elsevier Ltd.


Todd A.G.,Institute of Biomedical and Clinical Science | Shaw D.J.,Institute of Biomedical and Clinical Science | Morse R.,Institute of Biomedical and Clinical Science | Stebbings H.,University of Exeter | Young P.J.,Institute of Biomedical and Clinical Science
Biochemical and Biophysical Research Communications | Year: 2010

Childhood spinal muscular atrophy (SMA) is caused by a reduction in survival motor neuron (SMN) protein. SMN is expressed in every cell type, but it is predominantly the lower motor neurones of the spinal cord that degenerate in SMA. SMN has been linked to the axonal transport of β-actin mRNA, a breakdown in which could trigger disease onset. It is known that SMN is present in transport ribonucleoproteins (RNPs) granules that also contain Gemin2 and Gemin3. To further characterise these granules we have performed live cell imaging of GFP-tagged SMN, GFP-Gemin2, GFP-Gemin3, GFP-Gemin6 and GFP-Gemin7. In all, we have made two important observations: (1) SMN granules appear metamorphic; and (2) the SMN-Gemin complex(es) appears to localise to two distinct subsets of bodies in neurites; stationary bodies and smaller dynamic bodies. This study provides an insight into the neuronal function of the SMN complex. © 2010 Elsevier Inc. All rights reserved.


Booth C.A.,University of Bristol | Brown J.T.,Institute of Biomedical and Clinical science | Randall A.D.,University of Bristol | Randall A.D.,Institute of Biomedical and Clinical science
European Journal of Neuroscience | Year: 2014

A t(1;11) balanced chromosomal translocation transects the Disc1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated 'sag' and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5-25 APs at 50 Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input-output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity. © 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.


Timpson N.J.,University of Bristol | Nordestgaard B.G.,Copenhagen University | Harbord R.M.,University of Bristol | Zacho J.,Copenhagen University | And 3 more authors.
International Journal of Obesity | Year: 2011

Context:The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.Objective:Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.Participants and methods:The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them.Results:Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in logCRP of 1.03 kg m-2 (95% confidence interval (95% CI): 1.00, 1.07), P0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in logCRP of 0.24 kg m-2 (95% CI: 0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006).Conclusions:Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components. © 2011 Macmillan Publishers Limited. All rights reserved.

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