Splice site SNPs of phospholipase PLCXD3 are significantly associated with variant and sporadic Creutzfeldt-Jakob disease

BMC Medical Genetics

Richard SG Knight¹  Pascual Sanchez-Juan²  Matthew T Bishop¹ 

[1] National CJD Research & Surveillance Unit, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK;Neurology Department, University Hospital “Marqués de Valdecilla”. Fundación “Marqués de Valdecilla” (University of Cantabria) IFIMAV and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain

关键词: Phospholipase;    Susceptibility;    Neurodegeneration;    Infection;    Prion disease;   

Others  :  1122641
DOI  :  10.1186/1471-2350-14-91

 received in 2013-03-29, accepted in 2013-09-11,  发布年份 2013

【 摘 要 】

Background

Variant Creutzfeldt-Jakob disease is an infectious, neurodegenerative, protein-misfolding disease, of the prion disease family, originally acquired through ingestion of meat products contaminated with bovine spongiform encephalopathy (BSE). Public health concern was increased by the discovery of human-to-human transmission via blood transfusion. This study has verified a novel genetic marker linked to disease risk.

Methods

SNP imputation and association testing indicated those genes that had significant linkage to disease risk and one gene was investigated further with Sanger resequencing. Results from variant Creutzfeldt-Jakob disease were compared with those from sporadic (idiopathic) Creutzfeldt-Jakob disease and published controls.

Results

The most significant disease risk, in addition to the prion protein gene, was for the phosphatidylinositol-specific phospholipase C, X domain containing 3 (PLCXD3) gene. Sanger resequencing of CJD patients across a region of PLCXD3 with known variants confirmed three SNPs associated with variant and sporadic CJD.

Conclusions

These data provide the first highly significant confirmation of SNP allele frequencies for a novel CJD candidate gene providing new avenues for investigating these neurodegenerative prion diseases. The phospholipase PLCXD3 is primarily expressed in the brain and is associated with lipid catabolism and signal transduction.

【 授权许可】

   
2013 Bishop et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, Poser S, Pocchiari M, Hofman A, Smith PG: A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996, 347:921-925.
• [2]Ironside JW, Head MW, Bell JE, McCardle L, Will RG: Laboratory diagnosis of variant Creutzfeldt-Jakob disease. Histopathology 2000, 37:1-9.
• [3]Bishop MT, Pennington C, Heath CA, Will RG, Knight RS: PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism. BMC Med Genet 2009, 10:146. BioMed Central Full Text
• [4]Garske T, Ghani AC: Uncertainty in the tail of the variant Creutzfeldt-Jakob disease epidemic in the UK. PLoS One 2010, 5:e15626.
• [5]Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J: Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 1998, 352:703-704.
• [6]Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Ritchie D, Penney M, Hegazy D, Ironside JW: Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004, 203:733-739.
• [7]HPA: Summary results of the second national survey of abnormal prion prevalence in archived appendix specimens. Health Protection Report 2012, 6:17-22.
• [8]Cooper JD, Bird SM: UK dietary exposure to BSE in beef mechanically recovered meat: by birth cohort and gender. J Cancer Epidemiol Prev 2002, 7:59-70.
• [9]Bishop MT, Kovacs GG, Sanchez-Juan P, Knight RS: Cathepsin D SNP associated with increased risk of variant Creutzfeldt-Jakob disease. BMC Med Genet 2008, 9:31.
• [10]Sanchez-Juan P, Bishop MT, Aulchenko YS, Brandel JP, Rivadeneira F, Struchalin M, Lambert JC, Amouyel P, Combarros O, Sainz J: Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk. Neurobiol Aging 2011, 33:e1421-e1428. 1487
• [11]Mead S, Poulter M, Uphill J, Beck J, Whitfield J, Webb TE, Campbell T, Adamson G, Deriziotis P, Tabrizi SJ, et al.: Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study. Lancet Neurol 2009, 8:57-66.
• [12]Aulchenko YS, Ripke S, Isaacs A, Van Duijn CM: GenABEL: an R library for genome-wide association analysis. Bioinformatics (Oxford, England) 2007, 23:1294-1296.
• [13]Li Y, Willer C, Sanna S, Abecasis G: Genotype imputation. Annu Rev Genomics Hum Genet 2009, 10:387-406.
• [14]Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR: MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010, 34:816-834.
• [15]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, De Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81:559-575.
• [16]Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT: Data quality control in genetic case–control association studies. Nat Protoc 2010, 5:1564-1573.
• [17]Suh PG, Park JI, Manzoli L, Cocco L, Peak JC, Katan M, Fukami K, Kataoka T, Yun S, Ryu SH: Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 2008, 41:415-434.
• [18]Heinz DW, Essen LO, Williams RL: Structural and mechanistic comparison of prokaryotic and eukaryotic phosphoinositide-specific phospholipases C. J Mol Biol 1998, 275:635-650.
• [19]Gellatly SA, Kalujnaia S, Cramb G: Cloning, tissue distribution and sub-cellular localisation of phospholipase C X-domain containing protein (PLCXD) isoforms. Biochem Biophys Res Commun 2012, 424:651-656.
• [20]Torres M, Encina G, Soto C, Hetz C: Abnormal calcium homeostasis and protein folding stress at the ER: a common factor in familial and infectious prion disorders. Commun Integr Biol 2011, 4:258-261.