Lynn E. Pritchard
University of Oxford
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Featured researches published by Lynn E. Pritchard.
Nature Genetics | 1995
Simon T. Bennett; Anneke Lucassen; S. C. L. Gough; Elizabeth E. Powell; Dag E. Undlien; Lynn E. Pritchard; Marilyn E. Merriman; Yoshihiko Kawaguchi; Mark J Dronsfield; Flemming Pociot; Jørn Nerup; Nourdine Bouzekri; Anne Cambon-Thomsen; Kjersti S. Rønningen; Anthony H. Barnett; S. C. Bain; John A. Todd
The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1–kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By ‘cross–match’ haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent–of–origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.
Nature Genetics | 1998
Charles A. Mein; Laura Esposito; Michael G. Dunn; Gillian C.L. Johnson; Andrew E. Timms; Juliet V. Goy; Annabel N. Smith; Liam Sebag-Montefiore; Marilyn E. Merriman; Amanda Wilson; Lynn E. Pritchard; Francesco Cucca; Anthony H. Barnett; Stephen C. Bain; John A. Todd
Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (λs = 2.5; Refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at λs = 3 and lod = –2, of which two showed evidence of linkage: chromosome 10p13–p11 (maximum lod score (MLS) = 4.7, P = 3 × 10 –6, λs = 1.56) and chromosome 16q22–16q24 (MLS = 3.4, P = 6.5 × 10–5, λ s = 1.6). These and other novel regions, including chromosome 14q12–q21 and chromosome 19p13–19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.
Journal of Endocrinology | 2011
Nicola Whalley; Lynn E. Pritchard; David M. Smith; Anne White
Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic α-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and β-cell mass. The α-cell line, αTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25 mM) also increased GLP-1 but decreased glucagon secretion from αTC1-6 cells suggesting a switch in processing to favour GLP-1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in αTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused β-cell toxicity as evidenced by decreased glucose-stimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and β-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect β-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.
European Journal of Endocrinology | 2011
Philip G. Murray; Andrew P. Read; Indraneel Banerjee; Andrew Whatmore; Lynn E. Pritchard; Rick A. Davies; John Brennand; Anne White; Richard Ross; Peter Clayton
INTRODUCTION Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP. AIM To screen a group of children with CDGP for pathogenic sequence variants in LEP. PATIENTS AND METHODS Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin. RESULTS One child with CDGP was identified to be heterozygous for a novel missense variant (c.68C>G), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay. CONCLUSIONS This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo.
Nature | 1994
June L. Davies; Yoshihiko Kawaguchi; Simon T. Bennett; James B. Copeman; Heather J. Cordell; Lynn E. Pritchard; Peter W. Reed; Stephen C. L. Gough; Suzanne C. Jenkins; Sheila M. Palmer; Karen M. Balfour; Beth R. Rowe; Martin Farrall; Anthony H. Barnett; Stephen C. Bain; John A. Todd
Human Molecular Genetics | 1996
Lorenza Nisticò; Raffaella Buzzetti; Lynn E. Pritchard; Bart Van der Auwera; Giovannini C; Emanuele Bosi; Maria Teresa Martinez Larrad; Manuel Serrano Ríos; Chun-Chung Chow; Clive S. Cockram; K. H. Jacobs; C. Mijovic; Stephen C. Bain; Anthony H. Barnett; C L Vandewalle; Frans Schuit; Frans K. Gorus; Belgian Diabetes Registry; Roberto Tosi; Paolo Pozzilli; John A. Todd
Nature Genetics | 1994
Peter W. Reed; June L. Davies; James B. Copeman; Simon T. Bennett; Sheila M. Palmer; Lynn E. Pritchard; S. C. L. Gough; Yoshihiko Kawaguchi; Heather Jane Cordell; Karen M. Balfour; Suzanne C. Jenkins; Elizabeth E. Powell; Alain Vignal; John A. Todd
Human Molecular Genetics | 2002
Benjamin G. Challis; Lynn E. Pritchard; John Creemers; Jérôme Delplanque; Julia M. Keogh; Jian'an Luan; Nicholas J. Wareham; Giles S. H. Yeo; Sumit Bhattacharyya; Phillipe Froguel; Anne White; I. Sadaf Farooqi; Stephen O'Rahilly
Nature Genetics | 1992
S. C. Bain; Jan-Bas Prins; Catherine M. Hearne; Nanda Rodrigues; Bethan R Rowe; Lynn E. Pritchard; R.J. Ritchie; Jennifer R. S. Hall; Dag E. Undlien; Kjersti S. Rønningen; David B. Dunger; Anthony H. Barnett; John A. Todd
Kidney International | 1999
Albert C.M. Ong; Peter C. Harris; David R. Davies; Lynn E. Pritchard; Sandro Rossetti; Simon Biddolph; David J. Vaux; Nicola Migone; Christopher J. Ward