体系的・網羅的遺伝子解析によるALS関連遺伝子の探索
Contents
1. 10 0 3 2 4 A 5 6 Cronin et al 2007 8 000 m ALS 0 61 Al Chalabi et al WE 2010 1 ALS ALS ALS ALS ALS ALS 00555 6 10 ALS Pasinelli and Brown 2006 ALS 11 SODI NEFH ALS2 DCTNI VAPB SETX ANG FUS TARDBP DAO UBQLN2 Andersen and A Chalabi 2011 Mitchell et al 2010 Deng et al 2011 ALS Beleza Meireles and A Chalabi 20092. haploinsufficiency Del Bo et al 2011 ALS274 OP7N p G23X 6 5 Alu OPTN DK Alu mediated recombination Alu 300 10 6 Lander et al 2001 OPTN fiii 38 kb 38 Alu 2 4 5 Alu Alu Alu OPTN
3. ALS 52 2011 5 2 ALS ALSC1 TGF B 84 2011 9 D ALS BRE ZNF512B ALS 25 23 HA 2011 9 lida A Hosono N Sano M Kamei T Oshima S Tokuda T Kubo M Nakamura Y and Ikegawa S Novel deletion mutations of OPTN
4. ALS 12 II 5 2 1 TaqMan qPCR OPTN EE OPTN TaaMan 5 OZ7W 304 454 460 PEO RA 2 2 ALS OPTINO RE PCR a 304 1 4 kb PCR 256 454 460 4 kb 0 65 kb PCR c 9 OPTN 86 kb PCR 4 PCR 7 kb PCR M DNA x 2 3 304 460
5. B SNP p P413L ALS Gros Louis et al 2009 van Vught et al 2010 ALS GWAS H 2 9p21 2 10q26 3 5 ALS Z PER MEK F FGGY ITPR2 DPP6 KIFAP3 UNCISA Dunckley et al 2007 Schymick et al 2007a Landers et al 2009 Shatunov et al 2010 van Es et al 2007 van Es et al 2008 van Es et al 2009 C9ORF72 GGGGCC ALS ALS
6. 18 ZB1 ZNF512B myc ZB1 HA Cos7 24 d 3 5 III 4 ZNF512B ZB1 ZB1 ZNF512B ZNF512B ZB1 ZNF512B ZB1 10 GWAS
7. ALS 18 II 5 52 608 SNPs 3 1 ALS ZNF512B ALS SNP rs2275294 SNP 20 BRAK 913 3 ZNF512B 12 3 2 ZNF512B SNP rs2275294 SNP EEIZ ZNF512B ZNF512B 13kb G 17 4 CH ELT EPS A 3 3 TGF B ZNF512B a SNP rs2275294 C
8. Alu Deininger and Batzer 1999 Alu 3 Batzer et al 1996 older Alu Jo Jb intermediate Alu Sc Sx Sq younger Alu Y Ya Yb Deletion 2 younger Alu Y Deletion 1 3 11 Alu Jb Alu Sx Deletion 1 Alu Y amp Alu Jb Deletion 3 OP7N 2 ALS Hu ALS OZ7 OZESESEUX 1967720 SOME TARDBP OB S amp s amp 0t 3 5 ALS OPTN SODI ALS
9. 1 2 DAPI III 2 5 ZNF512B myc ZB1 HA negative control Cos7 HEEL 24 lysis buffer 20mM Tris pH 7 5 with 150mM NaCl 0 1 Nonident P 40 mye HA II 3 II 3 1 ZNF512B 17 ZNF512B ZNF512B Bd 3 4 ZNF512B data not shown II 3 2 ZNF512B
10. ALS OZ77V ALS OZ77V ALS ALS Maruyama et al 2010 C9ORF7220SALS FTD 1 6 GGGGCC ALS FTD 1 Renton et al 2011 DeJesus Hemandez et al 2011 DEY HHA CIS 23 ALS 700 1600 ALS 40 Genome wide association study GWAS Ct C9ORF72 ALS van Bs et al 2009 ALS C9ORF72 GGGGCC I 2 ALS AL
11. Sabatelli M et al 2012 v3 EG GWAS Chio et al 2009 Fernandez Santiago et al 2009 Daoud et al 2010 Fogh et al 2011 lida et al 2011a cu A I 2 ZNF512B IL ALS Optineurin l 1 ALS 1 OPTN OPTN Optineurin 577 BE3 14 7K Beau Li et al 199
12. Maruyama et al 2010 6 800 470 BIG KK OZ7W ALS Maruyama et al 2010 OPTN 2 OJ BEN loss of function gain of function Deletion 1 tk OPTN 16 Deletion 1 mRNA mRNA nonsense mediated RNA decay null Bhuvanagiri et al 2010 Deletion 2 3 OZ7W D null
13. OPTN 710 ALS 5 II 2 II 2 1 710 BID ALS 685 ALS 25 ALS Nakamura 2007 PCR OZP7W II 2 2 TaqMan PCR OPTNO 16 15 O TaqMan Primer Express software v2 0 Applied Biosystems 15 13
14. x 3 5 ZNF512B ZB1 ZNF512B ZB1 Cos7 ZNF512B ZB1 20 IV Akimoto C Morita M Atsuta N Sobue G Nakano I High Resolution Melting HRM Analysis of the Cu Zn Superoxide Dismutase SOD1 Gene in Japanese Sporadic Amyotrophic Lateral Sclerosis SALS Patients Neurol Res Int 165415 2011 Al Chalabi A Fang F Hanby MF Leigh PN Shaw CE Ye W Rijsdijk F An estimate of amyotrophic lateral sclerosis heritability using twin data J Neurol Neurosurg Psychiatry 81 1324 1326 2010 Andersen PM Al Chalabi A Clinical genetics of amyotrophic lateral sclerosis what do we really know Nat Rev Neurol 7 603 615 2011 Batzer MA Deininger PL Hellmann Blumberg U Jurka J Labuda D Rubin CM Schmid CW Zietkiewicz E Zuckerkandl E Standardized nomenclature for Alu repeats J Mol Evol 42 3 6 1996 Beleza Meireles A Al Chalabi A Genetic studies of amyotrophic lateral sclerosis controversies and perspectives Amyotroph Lateral Scler 10 1 14 2009 Bhuvanagiri M Schlitter AM Hentze MW Kulozik AE NMD RNA biology meets human genetic medicine Biochem J 430 365 377 2010 Chalasani ML Swarup G Balasubramanian D Optineurin and its mutants molecules associated with so
15. TaqMan 1 1 GC 1 TaqMan 3 4 3 4 4 OPTN RNase P Applied Biosystems PCR Hosono et al 2009 TaqMan Universal PCR Master Mix C Applied Biosystems II 2 3 7 PCR PCR 3730xl DNA Applied Biosystems DNA P io IL www repeatmasker org Il 3 OZ77V RepeatMasker
16. ALS 23 ALS D RA Ur ER ALS Comprehensive and systematic analysis of amyotrophic lateral sclerosis ALS related genes K Bk How M A L I 1 ALS 3 1 2 1814 ALS 4 II ALS Optineurin II 1 5 II 2 7 II 3 8 II 4 5 10 II 5 13 III ZNF512B IH 15 HI 2 16 HI 3 17 III 4 5 18 II 5 M 19 IV 21 V 25 VI 2011 2012 25 VIL 27 L amyotrophic lateral sclerosis ALS 2 3
17. ZNF512B C H rs2275294 ZNF512B 12 rs2275294 rs2275294 ZVF512B ALS C T 3 3 2 ALS C 15 ZNF512B TGF B TGF B ZNF512B TGF B SMAD E R 3 3 b ZNF512B TGF B
18. SMAD ZNF512B siRNA 888 3302 ZNF512B ALS ZNF512B TGF B rs2275294 ZNF512B ALS XI 3 3 o ALS ZNF512B ZNF512B ZB1 1 2 II 2 1 Cos7 SK N AS 10 Dulbecco s Modified Eagle Medium Off 37 C 5 CO III 2 2 ZNF
19. 4 5 PCR MHRA Cla PARES S 3 2 kb PCR 1 4 kb R 2 2 a PCR Deletion 1 4 5 Alu Fg 2 3 EB Maruyama et al 2010 Deletion 1 premature stop codon II 3 2 256 454 460 256 454 460 3 4 5 Ed 2 1 2 5 PCR PCR KER MARCIE 4kb PCR 4 kb PCR
20. lida et al 2011b ALS1 305 Pi EXT H8 4 244 ALS rs2275294 T C ZNF512B 12 P 9 3 X 101 AY ALE 1 32 95 CI 1 21 1 44 SNP ALS GWAS rs2275294 111 kb ALS TU HOt O Cibo rs2275294 ALS E MEB PE SNP R 3 1 ZNF512B DNA cDNA KIAA cDNA Nagase et al 1999 cDNA 5 919 bp G 893 13kb 17 Bd 3 2 mRNA
21. 2 p A93P 1 p A93P M HEIL ALS 3 8 ALS 0 29 ALS 1 6 Akimoto et al 2011 747 ALS 3 0 MEME ALS 0 29 ida et al 2012b OP7V MEE ALS SODIO 1 5 TARDBP O 77V 1 Maruyama et al 2010 OP7N 2 PCR PCR OZ77V TaqMan OZ7V
22. REA F 31 ax u 0ogZ g 7NZ AU C Bel S E STV 1 0 8LXOS SOLIMIN SZ BL 92L00VNHON 9 JJ OLGWVS LON SOrVNa NE ACLSANZ 6Z9 CZS mg mg qJ 0c oo BOD COOO A Oo N OO OO EN OQO N ND ND O05 QOO 20200 o o N a NN NN ON ONN NOOO A N N N GO QQ ON N OUUU Wo N gt N N OO OO Qc OBRBONOCO A o a oo O OD WAN NO o o N BO I TRY E ES IV A Li sdNS 809 S IY E we Ge Sy ey 32 EL BY O CGAEBAT GOPCIGINZ e eps zr gp FY Er i Cy 3 tu Core HO x asses a B F G lt AFI LD 9X cI 33 dors v6cGLcecs dNSEESTV 910 2LGHdNZ J491 JS OL SL 02 S6 c0 0 d wn 2834087 LGJNZ 9 gs Gr g 45S1 6 6 A1IAI1OB 9SB GJIOn eAne aJ 9 D1 q HERK SIV L MSH uoN yoom 9 alalle ASIH ialouold 0 L00 0 gt d oz amp c or amp Bt sec LS4NZ n o ataca 8 lt ULL YH MB O lt 9 4 91 108 WEST 0 m 34 LEVE Og l S4NZ 6 35 EH Usigzagsects3NZ 9 6 ss UI1OV USD Laz pe66el VH ma MN 92z19JNZ pe66el oAWN ZILGHNZ gZ LAZ VH dl les 1 dgZLS
23. TT E Promoter ZVF512B Non risk T ZVF512B SNP rs2275294 O T Risk allele C 3 ZNF512B SNP rs2275294 C b ZNFSIZB 14 TGF B VEO SS EST EE TGF B signaling E SBE4 4 X Smad binding element ZNF512B TGF B c ALS ZNF512B TGF B rs2275294 C 19 F572B ALS X 3 4 ZNF512B
24. 650bp PCR 2 3 PCR IA fy KE Deletion 2 2 5 Alu 4 XI 2 3 460 E 4 3 OPTN OF null OPTN II 3 3 9 9 1 2 3 4 2 4 EBS o 5 1 10 kb 5 1ong PCR OP77V
25. ALS 597 ALS 3 OZ7 5 pb Q398X ALS p EB478G Optineurin Optineurin NF KB Optineurin ALS MARCUS Tua uE p E478G p E478G i ALS O 7 1 ida et al 2012a Maruyama et al OPTN 0 HE Maruyama et al 2010 OP7VW
26. TaqMan PCR 710ALS 5 3 Maruyama et al 2010 4 BU CINE act BORE C N M E ALS ET RAIL 470 Alu ALS OPTN Alu mediated recombination 3 Alu II 3 1 304 304 5 2 1 3 4 6 5
27. Dunckley T Huentelman MJ Craig DW Pearson JV Szelinger S Joshipura K Halperin RF Stamper C Jensen KR Letizia D et al Whole genome analysis of sporadic amyotrophic lateral sclerosis N Engl J Med 357 775 788 2007 Fernandez Santiago R Sharma M Berg D Illig T Anneser J Meyer T Ludolph A and Gasser T No evidence of association of FLJ10986 and ITPR2 with ALS in a large German cohort Neurobiol Aging 32 551e1 4 2009 Fogh I D Alfonso S Gellera C Ratti A Cereda C Penco S Corrado L Soraru G Castellotti B Tiloca C et al No association of DPP6 with amyotrophic lateral sclerosis in an Italian population Neurobiol Aging 32 966 967 2011 Gros Louis F Andersen PM Dupre N Urushitani M Dion P Souchon F D Amour M Camu W Meininger V Bouchard JP et al Chromogranin B P413L variant as risk factor and modifier of disease onset for amyotrophic lateral sclerosis Proc Natl Acad Sci U SA 106 21777 21782 2009 Hosono N Kato M Kiyotani K Mushiroda T Takata S Sato H Amitani H Tsuchiya Y Yamazaki K Tsunoda T et al CYP2D6 genotyping for functional gene dosage analysis by allele copy number detection Clin Chem 55 1546 1554 2009 lida A Takahashi A Deng M Zhang Y Wang J Atsuta N Tanaka F Kamei T Sano M Oshima S et al Replication analysis of SNPs on 9p21 2 and 19p13 3 with amyotrophic lateral sclerosis in East Asians Neurobiol Aging 32 757e13 4 2011a lida A Takahashi A Kubo M Sai
28. 92 kb 5 Bd 2 2 c OZ77V 4 Alu II 4 710 BID ALS OZ77V 5 PIO IR ALS long PCR 7 kb O PCR PCR R Deletion 3 OZP77V 85 8 kb Alu Y Bd 2 4 BE 5 OPTN deletion hotspot A 5 OPTNO KK 200 filo B a 3 T E Maruyama et al 2010
29. OZ 7 304 460 DNA OZ7 2 OPTNO 5 6 OF 2 4 9 OZ7W HIRE CH ABLE Alu BJ TaqMan CA PCR RPL5P25 L5 25 CCDC3 coiled coil domain containing 3 DNA 13 2 5 ALS OPTN XK EE OZ7W 14 III ZNF512B HI 1 ALS SNP JSNP 52 608 SNPs
30. Corbo M Giannini F et al C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population Neurobiol Aging Epub ahead of print 2012 Schymick JC Scholz SW Fung HC Britton A Arepalli S Gibbs JR Lombardo F Matarin M Kasperaviciute D Hernandez DG et al Genome wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls first stage analysis and public release of data Lancet Neurol 6 322 328 2007a Schymick JC Talbot K Traynor BJ Genetics of sporadic amyotrophic lateral sclerosis Hum Mol Genet 16 R233 242 2007b Shatunov A Mok K Newhouse S Weale ME Smith B Vance C Johnson L Veldink JH van Es MA van den Berg LH et al Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries a genome wide association study Lancet Neurol 9 986 994 2010 van Es MA Van Vught PW Blauw HM Franke L Saris CG Andersen PM Van Den Bosch L de Jong SW van t Slot R Birve A et al ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis a genome wide association study Lancet Neurol 6 869 877 2007 van Es MA van Vught PW Blauw HM Franke L Saris CG Van den Bosch L de Jong SW de Jong V Baas F van t Slot R et al Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis Nat Genet 40 29 31 2008 van Es MA Veldink JH Saris CG Blauw HM van Vught PW Birve A Lemmens R Schelhaas H
31. Y Kinoshita Y Kamada M Nodera H Suzuki H et al Mutations of optineurin in amyotrophic lateral sclerosis Nature 465 223 226 2010 Mitchell J Paul P Chen HJ Morris A Payling M Falchi M Habgood J Panoutsou S Winkler S Tisato V et al Familial amyotrophic lateral sclerosis is associated with a mutation in D amino acid oxidase Proc Natl Acad Sci U S A 107 7556 7561 2010 Nagase T Ishikawa K Kikuno R Hirosawa M Nomura N Ohara O Prediction of the coding sequences Of unidentified human genes XV The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro DNA Res 6 337 345 1999 Nakamura Y The BioBank Japan Project Clin Adv Hematol Oncol 5 696 697 2007 Pasinelli P Brown RH Molecular biology of amyotrophic lateral sclerosis insights from genetics Nat Rev Neurosci 7 710 723 2006 Renton AE Majounie E Waite A Sim n S nchez J Rollinson S Gibbs JR Schymick JC Laaksovirta H van Swieten JC Myllykangas L et al A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21 linked ALS FTD Neuron 72 257 268 2011 Rezaie T Child A Hitchings R Brice G Miller L Coca Prados M Heon E Krupin T Ritch R Kreutzer D et al Adult onset primary open angle glaucoma caused by mutations in optineurin Science 295 1077 1079 2002 23 Sabatelli M Conforti FL Zollino M Mora G Monsurro MR Volanti P Marinou K Salvi F
32. in amyotrophic lateral sclerosis in Japanese Neurobiology of Aging in press 2012 26 HO XN LdO f dOdb uewbel 1 28 O9v 3f tGr 6 zh VOE i I 14 96 0S L 14 96 0S 0 0 MRNA 0 Nadel e F SV T qJ G m d N LdO Po p 1 9L GL bl I troL 6 8 4 9 Giz ueybe ci vie 27 0 65 28 OZ7W 2 2 ALSI M ld 6 v NA Ng x 0944 TK N dO YA XTA AT K GEN UV V TI Bii FX 1 m n A N 1 A A A l A f h J N j M h f j i Jt IN aw j 1 WWE A A A A A j L JV IN INS V I ILLNM M MY NJ V V VV TAL MI V Y V J EE 1 V 1 VJ V v pay kh tJ ALR 1 Ul Bi j f V U A f j V BH l f v v f 1j l l f 29 d 0Z aY s co E M W dO S 2 6 6 v e p CD Y bi x Hii d P o Pal EG x Nido ody 2022 o m P Y XS vo q8b dOd1qY0Z dd1dY06 vo q09 HOd10 08 VO uewbe1qy0L uew be xy u ube1Zx VI qY9Z ue DB 5X UeINbeLSx3 30 SYXNIdOXHULEgISITY QIE G Z J OMY OO 26 ETE GC FI Sim TRIES WV 9 Pf 2 Aoualoyynsulojdey ZHL Og E S XEHI S NOD v Ay 26 Fl X I S 14 3 2uon l p 0 NIV dO SIVO ea oL COR EEE e NIdO 91V s 5g4pg d de6V d FEA us Se ee
33. 512BcDNA pCDNA3 1A myc His ZNF512B 16 ZBI cDNA p CMV HA DNA II 2 3 TransIT DNA BE TransIT TransIT 24 48 III 2 4 ZNF512B 4 0 1 Triton X100 2
34. 8 16 1 ZIP C NF KB Chalasani et al 2009 Optineurin 1IV RAB8 NEMO Chalasani et al 2009 OZ7W 2002 3 p B50K 691 692insAG p R545Q p M98K 253 x Rezaie et al 2002 Maruyama et al 2010 OZ7 ALS Maruyama et al 2010 689 ALS 92
35. ANZ pebbe oAp Laz z mSZLSANZ g8c LGJNZ 9AW dl 91esA 36
36. J Groen EJ Huisman MH et al Genome wide association study identifies 19p13 3 UNC13A and 9p21 2 as susceptibility loci for sporadic amyotrophic lateral sclerosis Nat Genet 41 1083 1087 2009 van Vught PW Veldink JH van den Berg LH P413L CHGB is not associated with ALS susceptibility or age at onset in a Dutch population Proc Natl Acad Sci U S A 107 E77 2010 24 V ALS FET VL 2011 2012 1
37. S MISE ALS lt ALS ALS Schymick et al 2007b MSE ALS GWAS ED single nucleotide polymorphism SNP In TEE VEGF El APEX ANG CHMP2B NEFH Paraoxonase 30 Schymick et al 2007b NEFH APEX ANG ALS ALS
38. me forms of glaucoma Ophthalmic Res 42 176 184 2009 Chio A Schymick JC Restagno G Scholz SW Lombardo F Lai SL Mora G Fung HC Britton A Arepalli S et al A two stage genome wide association study of sporadic amyotrophic lateral sclerosis Hum Mol Genet 18 1524 1532 2009 Cronin S Hardiman O Traynor BJ Ethnic variation in the incidence of ALS a systematic review Neurology 68 1002 1007 2007 Daoud H Belzil V Desjarlais A Camu W Dion PA Rouleau GA Analysis of the UNC13A gene as a risk factor for sporadic amyotrophic lateral sclerosis Arch Neurol 67 516 517 2010 Deininger PL Batzer MA Alu repeats and human disease Mol Genet Metab 67 183 193 1999 DeJesus Hernandez M Mackenzie IR Boeve BF Boxer AL Baker M Rutherford NJ Nicholson AM Finch NA Flynn H et al Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p linked FTD and ALS 21 Neuron 72 245 56 2011 Del Bo R Tiloca C Pensato V Corrado L Ratti A Ticozzi N Corti S Castellotti B Mazzini L Soraru G et al Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis J Neurol Neurosurg Psychiatry 82 1239 1243 2011 Deng HX Chen W Hong ST Boycott KM Gorrie GH Siddigue N Yang Y Fecto F Shi Y Zhai H et al Mutations in UBQLN2 cause dominant X linked juvenile and adult onset ALS and ALS dementia Nature 477 211 215 2011
39. to S Hosono N Ohnishi Y Kiyotani K Mushiroda T Nakajima M Ozaki K et al A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese Hum Mol Genet 20 3684 3692 2011b lida A Hosono N Sano M Kamei T Oshima S Tokuda T Kubo M Nakamura Y Ikegawa S Optineurin mutations in Japanese amyotrophic lateral sclerosis J Neurol Neurosurg Psychiatry J Neurol Neurosurg Psychiatry 83 233 235 2012a 22 lida A Kamei T Sano M Oshima S Tokuda T Nakamura Y lkegawa S Large scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese Neurobiol Aging 33 786 790 2012b Lander ES Linton LM Birren B Nusbaum C Zody MC Baldwin J Devon K Dewar K Doyle M FitzHugh W et al 2001 Initial sequencing and analysis of the human genome Nature 409 860 921 2001 Landers JE Melki J Meininger V Glass JD van den Berg LH van Es MA Sapp PC van Vught PW McKenna Yasek DM Blauw HM et al Reduced expression of the Kinesin Associated Protein 3 KIFAP3 gene increases survival in sporadic amyotrophic lateral sclerosis Proc Natl Acad Sci U S A 106 9004 9009 2009 Li Y Kang J Horwitz MS Interaction of an adenovirus E3 14 7 kilodalton protein with a novel tumor necrosis factor alpha inducible cellular protein containing leucine zipper domains Mol Cell Biol 18 1601 1610 1998 Maruyama H Morino H Ito H Izumi Y Kato H Watanabe
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