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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. Source


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. Source


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. Source


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. Source


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. Source

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