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1. gt Mouse Progranulin ELISA Kit re CircuLex Users Manual For Research Use Only Not for use in diagnostic procedures 4 gt ELISA Kit for Measuring Mouse Progranulin N CircuLex Mouse Progranulin ELISA W Cat CY 8108 amp Tine SING a coccatessucncsnmoieetocantatsecaacoannslesten 1 gt trat A eee E ene een arr ern eee 1 y DIAS OIN aiisis vesrodaddoeceseepansanaaoecanentaeeasess 2 ww Principle of the Assay 2 3 a Materials Provided sccscaccisccsavasnesocesencexsnes 3 Q Materials Required but not Provided 4 gt Precautions and Recommendation 5 Q Sample Collection and Storage 0 0 6 amp Detailed Prot sosateccssactanctsdasnsatacatenseaasecnees 7 8 Ca PATIOS lt a sarecicnccsiusiccenntenscheeatdueaseansecanes 9 oe Measurement Range 9 7 Troubles WO Ota sicccsiccesetsnsissse somanaguusieaccenaces 9 Reagent Stability ississsssssssetsssnsveievcssiosiznaasevesy 9 amp Assay Characteristics ccssessessseesreeeees Referent Snares eireas lt o Related Products ccceesscceessseeesseseeeeeme 4 Intended Use measurement of mouse progranulin erum plasma cell culture supernatant and other biological prog eA p p 2 media 7 This assay kit is for research Eday and not for use in diagnostic or therapeutic procedures AN The CycLex Research Product o Progranulin ELISA Kit is used for the quantitative Storage e Upon receipt store ae hpoicote2. w g S 2 a z 3 z a of 3 Z Sample 1 e Sample 2 Sample 3 0 4 0 6 Sample mouse serum 0 8 1 Dilution factor Roa CY 8108 12 Version 151113 ge Mouse Progranulin ELISA Kit L ircuLex User s Manual For Research Use Only Not for use in diagnostic procedures 4 References 1 Daniels R Daniels E He Z and Bateman A Progranulin acrogranin PC cell deriy rowth factor granulin epithelin precursor is expressed in the placenta epidermis microvascufasure and brain during murine development Developmental Dynamics vol 227 no 4 pp 593 5 003 2 He Z and Bateman A Progranulin granulin epithelin precursor ere Sth factor acrogranin mediates tissue repair and tumorigenesis Journal of Molecular Medigag vol 81 no 10 pp 600 612 2003 3 Bhandari V Palfree R G Bateman A 1992 Isolation and sequence of the Quin precursor cDNA from human bone marrow reveals tandem cysteine rich granulin domgigs Proc Natl Acad Sci U S A 89 1715 1719 NA Y 4 Daniel R He Z Carmichael K P Halper J Bateman A 2000 Cellular localization of gene expression for progranulin J Histochem Cytochem 48 999 100 5 Daniel R Daniels E He Z Bateman A 2003 Prograni acrogranin PC cell derived growth factor granulin epithelin precursor is expressed in the Place ta epidermis microvasculature and brain during m
3. using a squirt bottle multi channel pipette manifold dispenser or microplate washer 9 Add 100 uL of Substrate Reagent Avoid MNN the microtiter plate to direct sunlight Covering the plate with e g aluminum foil is recommeng y Return Substrate Reagent to 4 C immediately after the necessary volume is removed lt Incubate the plate at room temperatu 25 C for 10 20 minutes shaking at ca 300 rpm on an orbital microplate shaker The incubyon time may be extended up to 30 minutes if the reaction temperature is below 20 C Add 100 uL of Stop Solution each well in the same order as the previously added Substrate Reagent x 12 Measure absorbance in caven using a spectrophotometric microplate reader at dual wavelengths of 450 540 nm Dual waveJtagths of 450 550 or 450 595 nm can also be used Read the microplate at 450 nm if only a sin velength can be used Wells must be read within 30 minutes of adding the Stop Solution Note 1 Completeremoval of liquid at each step is essential to good performance After the last wash remo ny remaining Wash Buffer by aspirating or decanting Invert the plate and blot it agai clean paper towels Note 2 R le standard curves are obtained when either O D values do not exceed 0 25 units for the zero concentration or 3 0 units for the highest standard concentration The plate ould be monitored at 5 minute intervals for approximately 30 minutes Note 3 If the microplate reader is not
4. Oy aminated with infectious agents Do not ingest expose to open wounds or breathe across ear protective gloves and dispose of biological samples properly handli p Solution O nw a Qe amp eo ate CY 8108 5 Version 151113 e CAUTION Sulfuric is a strong acid Wear disposable gloves and eye protection when o AO Mouse Progranulin ELISA Kit CircuLex Users Manual For Research Use Only Not for use in diagnostic procedures 4 A Q O Q Sample Collection and Storage 3 Serum Use a serum separator tube and allow samples to clot for 60 30 minutes Copuatfase the samples at 4 C for 10 minutes at 1 000 x g Remove serum and assay immediately or stor Amples on ice for up to 6 hours before assaying Aliquots of serum may also be stored at below 70 r extended periods of time Avoid repeated freeze thaw cycles amp Y Plasma Collect plasma using EDTA Naz as the anticoagulant If possible colle e plasma into a mixture of EDTA Na2 and Futhan FUT175 to stabilize the sample against Gpontaneous in vitro complement activation Immediately centrifuge samples at 4 C for 15 minufgg at 1 000 x g Assay immediately or store samples on ice for up to 6 hours before assaying Aliqu f plasma may also be stored at below 70 C for extended periods of time Avoid repeated freeze t cycles Note Citrate plasma has not been validated for use in this assay gt Cell culture supernatant Remove any particulates by centr
5. and addition of Substrate Reagent Do not allow the plate to dry out Add Substrate Reagent immediately after wash 7 Reage Stability All M reagents included in the CycLex Research Product CircuLex Mouse Progranulin ELISA Kit have been tested for stability Reagents should not be used beyond the stated expiration date Upon rec kit reagents should be stored at 4 C except the reconstituted Mouse Progranulin Standard must b red at below 70 C Coated assay plates should be stored in the original foil bag sealed by the zip and containing a desiccant pack LS at CY 8108 9 Version 151113 S C A CircuLex Users Manual For Research Use Only Not for use in diagnostic procedures 4 Assay Characteristics 3 RY 1 Sensitivity gt Mouse Progranulin ELISA Kit re The limit of detection defined as such a concentration of mouse progranulin giving absor A higher than mean absorbance of blank plus three standard deviations of the absorbance of bla blank 3SD blank is better than 190 pg mL of sample Q Dilution Buffer was pipetted into blank wells o Typical Standard Curve Meg Standard Curve Roa CY 8108 10 Version 151113 amp lt C CircuLex Users Manual For Research Use Only Not for use in diagnostic procedures gt Mouse Progranulin ELISA Kit re 2 Precision O Intra assay Precision Precision within an assay lt Three samples of known concentration were
6. at 4 C e Don t expose reaga 0 excessive light gt o gL A ate CY 8108 1 Version 151113 o c Mouse Progranulin ELISA Kit L ircuLex User s Manual For Research Use Only Not for use in diagnostic procedures 4 A Q O Q Introduction 3 Progranulin PGRN also called granulin epithelin proepithelin prostate cancer cell derivg Growth factor acrogranin or paragranulin is a cysteine rich protein that is typically secreted highly glycosylated 88kDa form 1 2 PGRN is a growth factor involved in the regulatio multiple processes including cell proliferation tumorigenesis wound healing development an inflammation PGRN is widely expressed in epithelia bone marrow immune cells solid organs Q the nervous system both during development and in adulthood 3 7 In 2006 mutations in PGRN were discovered to be a cause of frontotemporg feb degeneration FTLD with ubiquitinated TDP 43 positive inclusions 6 8 10 12 13 Moyg than 70 mutations in PGRN almost all of which result in null alleles have been identified in FTLD ptients A few causative missense mutations also result in reduced levels of PGRN 10 PGRN can be found in adipose tissue epithelial tissue gastrointestinal wy reproductive organs and so forth 11 Previous studies have demonstrated that increased gene RN of PGRN stimulates cancer cell division invasion and against anoikis promoting tumor fond ion 2 It has been shown that P
7. tested sixteen times on one plate to assess ijwa assay precision RS e Intra assay Within Run n 16 CV 2 0 2 7 amp Sai mouse serum Mouse progranulin conc ug mL af le 1 le 2 le 3 A 1 6 86 4 73 2 51 lt 2 6 99 4 65 2 41 wD 3 7 20 471 2 42 N 4 7 51 4 63 238 RG 5 7 43 4 86 2 45 amp 6 7 09 4 60 2 47 Yo 7 7 14 4 57 242 j 8 7 01 4 59 2 39 9 7 14 4 84 2 57 10 7 25 4 74 2 56 11 7 41 4 69 49 2 7 09 4 78 2 56 13 7 50 4 81 2 50 14 7 36 4 64 2 50 15 7 30 4 63 2 53 16 7 13 4 80 2 50 MAX 7 51 4 86 2 57 MIN 6 86 4 57 2 38 MEAN 7 21 4 71 2 48 S D 0 19 0 09 0 06 CY 2 7 2 0 2 4 Q g oe Roa CY 8108 11 Version 151113 S C CircuLex Inter assay Precision Precision between assays For Research Use Only Not for use in diagnostic procedures N e Inter assay Run to Run n 5 CV 3 5 7 3 Ss Three samples of known concentration were tested in five separate assays to assess interasay precision Mouse progranulin conc ug ml 3 Linearity Three samples were diluted with Dilution Serum 1 Serum 2 6 80 420 6 47 3 88 7 07 4 62 6 83 3 97 6 56 3 97 7 07 4 62 6 47 3 88 6 74 4 13 0 238 0 300 3 5 7 3 User s Manual gt Mouse Progranulin ELISA Kit re Serum 3 o Ad M9 Us LA de w mir mh hw bh R m Up ia Bugs assayed after dilution The neat sample was set to 1 The neat sample was 500 fold diluted a ed in the Assay Procedure e gt
8. 920 924 10 Shankaran Pd Capell A Hruscha A T Fellerer K Neumann M Schmid B Haass C 2008 Missense itations in the progranulin gene linked to frontotemporal lobar degeneration with ubiquiti unoreactive inclusions reduce progranulin production and secretion J Biol Chem 283 144 1753 11 a ae D Malik S Vinogradova A et al Structure dissection of human progranulin identifies 1 folded granulin epithelin modules with unique functional activities Protein Science vol 17 N 4 pp 711 724 2008 A Q O Q A Roa CY 8108 13 Version 151113 o AO Mouse Progranulin ELISA Kit L ircuLex User s Manual 12 13 14 15 16 For Research Use Only Not for use in diagnostic procedures Boss u P Salani F Alberici A et al Loss of function mutations in the progranulin gene are rela Mo pro inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients Joun of Neuroinflammation vol 8 article 65 2011 lt R Finch N Baker M Crook R et al Plasma progranulin levels predict progranulin mutagighn status in frontotemporal dementia patients and asymptomatic family members Brain vol 482 no 3 pp 583 591 2009 Tang W Lu Y Tian QY et al The growth factor progranulin binds to tnf recep Bind is therapeutic against inflammatory arthritis in mice Science vol 332 no 6028 pp 478 48 01l Youn BS Bang SI Kl ting N et al Serum progranulin a be associated with mac
9. Antibody One bottle containing 12 mL of HRP horseradish peroxidase conjugated anti se progranulin antibody Ready to use Substrate ent One bottle containing 20 mL of the chromogenic substrate tetra methylbenzidine TMB to use Stop o tion One bottle containing 20 mL of 1 N H2SO Ready to use e ate CY 8108 3 Version 151113 o c A CircuLex Users Manual gt Mouse Progranulin ELISA Kit re For Research Use Only Not for use in diagnostic procedures 4 Materials Required but not Provided 3 e Pipettors 2 20 uL 20 200 uL and 200 1000 uL precision pipettors with disposable tips RS N Precision repeating pipettor N Orbital microplate shaker g e Microcentrifuge and tubes for sample preparation 2 e Vortex mixer oO e Optional Microplate washer Manual washing is possible but not proggie e Plate reader capable of measuring absorbance in 96 well plates at N wavelengths of 450 540 nm Dual wavelengths of 450 550 or 450 595 nm can also be used ThEPlate can also be read at a single wavelength of 450 nm which will give a somewhat higher e Optional Software package facilitating data generation q analysis 500 or 1000 mL graduated cylinder e Reagent reservoirs amp Y Deionized water of the highest quality wW O e Disposable paper towels Xi ate CY 8108 4 Version 151113 o c S Mouse Progranulin ELISA Kit 9 CircuLex Users Manual For Re
10. GRN could restrain rheumatoid arthritis b amp inding directly to tumor necrosis factor receptors TNFR and play an anti inflammatory role in t rocesses 14 In addition it was reported that circulating PGRN levels are elevated in patient th type 2 diabetes 15 Moreover increased plasma PGRN levels are associated with impaire glucose tolerance rather than impaired fasting glucose 16 Although type 2 diabetes is often acco anied by obesity the respective role of elevation of circulating PGRN levels in obesity and type 2 G betes remains to be elucidated Principle of the Assay lt lt The CycLex Research Product CircuLex MQ Progranulin ELISA Kit employs the quantitative sandwich enzyme immunoassay technique An antibody specific for mouse progranulin is pre coated onto a microplate Standards and samples petted into the wells and the immobilized antibody binds any mouse progranulin present After ing away any unbound substances an HRP conjugated antibody specific for mouse progranulintig added to the wells Following a wash to remove any unbound antibody HRP conjugate the reining conjugate is allowed to react with the substrate H202 tetramethylbenzidine The rea on is stopped by addition of acidic solution and absorbance of the resulting yellow product is meas Ot at 450 nm The absorbance is proportional to the concentration of mouse progranulin A sani is constructed by plotting absorbance values versus mouse progranulin concentrat
11. capable of reading absorbance greater than the absorbance of the highest standard perform a second reading at 405 nm A new standard curve constructed gL using the values measured at 405 nm is used to determine mouse progranulin concentration of off scale samples The readings at 405 nm should not replace the on scale readings at 450 nm ate CY 8108 8 Version 151113 o AO A L ircuLex User s Manual For Research Use Only Not for use in diagnostic procedures 4 Calculations Average the duplicate readings for each standard control and sample and subtract the a Zero standard optical density Plot the optical density for the standards versus the concentr of the standards and draw the best curve The data can be linearized by using log log paper ale analysis may be applied to the log transformation To determine the mouse progranulin Qycentration of gt Mouse Progranulin ELISA Kit re each sample first find the absorbance value on the y axis and extend a horizontal li the standard curve At the point of intersection extend a vertical line to the x axis and read the cggfesponding mouse progranulin concentration If the samples have been diluted the concentration r rom the standard curve must be multiplied by the dilution factor R Y 1 The dose response curve of this assay fits best to a sigmoidal para logistic equation The results of unknown samples can be calculated with any computer progfYa
12. eption of 10X Wash Buffer and Mouse Progran tandard deionized distilled water ddH2O Mix well Store at 4 C for weeks or 20 C for long term 1 Prepare a working solution of Wash Buffer by adding 100 mL of Ss Wash Buffer to 900 mL of storage C 2 Reconstitute Mouse Progranulin Standard with 0 5 mL ddH20 After dissolved by gently mixing immediately dispense in small aliquots e g 100 iL to micro centrifuge tubes and store at below 70 C to avoid repeated freezing and thawing T ncentration of the mouse progranulin in vial should be 240 ng mL which is referred as a Mast andard of mouse progranulin Prepare Standard Solutions as follows CA Use the Master Standard to produce a dilu eries below Mix each tube thoroughly before the next transfer The 24 ng mL standard Std 1 serves as the highest standard The Dilution Buffer serves as the zero standard Blanks S Volume of Sta Qa Dilution Buffer Concentration Std 1 60 uL of Master TA ng mL 540 uL 24 ng mL Std 2 300 uL of Std 1 24 e a 300 uL 12 ng mL Std 3 300 uL of Std 2 1 g mL 300 uL 6 ng mL Std 4 300 uL of Std 3 g mL 300 uL 3 ng mL Std 5 300 uL of sae ng mL 300 uL 1 5 ng mL Std 6 300 uL of St 5 1 5 ng mL 300 uL 0 75 ng mL Std 7 300 uL ggi 6 0 75 ng mL 300 uL 0 375 ng mL Blank 300 uL 0 ng mL Standar sffould be aliquoted and stored at below 70 C immediately Avoid multiple freeze and N
13. ifugatio ind assay immediately or aliquot and store samples at below 70 C Avoid repeated freeze thaw cy Other biological samples Remove any particulates by centridugation and assay immediately or aliquot and store samples at below 70 C Avoid repeated freeze tha eycles gt NOTE THE ABOVE PROCEDURES ARE IN BNDED ONLY AS A GUIDELINE THE OPTIMAL EXPERIMENTAL CO NS WILL VARY DEPENDING ON THE PARAMETERS BEING INVESTIGATED AND MUST BE DETERMINED BY THE INDIVIDUAL USER NO WAR TY OR GUARANTEE OF PERFORMANCE USING THESE PROCEDURES R ADE OR IMPLIED v amp Xi ate CY 8108 6 Version 151113 o c Mouse Progranulin ELISA Kit L ircuLex User s Manual For Research Use Only Not for use in diagnostic procedures A Q O Q lt Detailed Protocol 3 The CycLex Research Product CircuLex Mouse Progranulin ELISA Kit is prowiplest with removable strips of wells so the assay can be carried out on separate occasions using only thesaumber of strips required for the particular determination Since experimental conditions may vary aliquot of the Mouse Progranulin Standard within the kit should be included in each assay a calibrator Disposable pipette tips and reagent troughs should be used for all liquid Nes to avoid cross contamination of reagents or samples Y Q Preparation of Working Solutions All reagents need to be brought to room temperature prior to the assay reagents are supplied ready to use with the exc
14. ions alibrators and concentrations of unknown samples are determined using this standard curve A Ss oO B O RS Q e ate CY 8108 2 Version 151113 o AO CircuLex Users Manual For Research Use Only Not for use in diagnostic procedures gt Mouse Progranulin ELISA Kit re gt Summary of Procedure l Add 100 uL of diluted samples to the wells SS 4 Incubate for 1 5 hours at room temp K Wash the wells 74 y Add 100 uL of HRP conjugated anti mouse progranulin A body 4 Incubate for 1 5 hours at room tenp Wash the wells aS 4 gt Add 100 uL of Substrate Reagent gt 4 Incubate for 10 20 e at room temp Add 100 uL of Stop Solution i o Measure absorbance at 450 nm KG Materials Provided x ee OOo All samples and standards should be assay MY duplicate The following components are supplied and are sufficient for the one 96 well microplate gj Microplate One microplate supplied real to use with 96 wells 12 strips of 8 wells in a foil zip lock bag with a desiccant pack Wells are eyed with anti mouse progranulin antibody as a capture antibody 10X Wash Buffer One bottle conning 100 mL of 10X buffer containing Tween 20 amp Dilution Buffer One bottle ining 50 mL of 1X buffer use for standard and sample dilution Ready to use a Mouse Progranulin grave One vial containing 120 ng of lyophilized recombinant mouse progranulin O HRP conjugated etection
15. m having a 4 parameter logistic function It is important to make an appropriate mathematical Austment to accommodate for the dilution factor wy 2 Most microtiter plate readers perform automatic calculations of lyte concentration The calibration curve is constructed by plotting the absorbance Y of Kbraors versus log of the known concentration X of calibrators using the 4 parameter fungtion Alternatively the logit log function can be used to linearize the calibration curve i e logit ofghtorbance Y is plotted versus log of the known concentration X of calibrators RS Measurement Range amp Y The measurement range is 0 375 ng mL to 2 ink Any sample reading higher than the highest standard should be diluted with Dilution Buff igher dilution and re assayed Dilution factors need to be taken into consideration in calculating thg mouse progranulin concentration Troubleshooting Q 1 All samples and standards should b assayed in duplicate using the protocol described in the Detailed Protocol Incubation times or peratures significantly different from those specified may give erroneous results Q 2 Poor duplicates accompafeed by elevated values for wells containing no sample indicate insufficient washing If all instructi s in the Detailed Protocol were followed accurately such results indicate a need for washer mai ce 3 Overall low sign ay indicate that desiccation of the plate has occurred between the final wash
16. ote Do not a Repeating pipette Change tips for every dilution Unused portions of Master thaw T Sampie 8 aration Dilu mples with Dilution Buffer and plasma samples may require 500 to 1 000 fold dilution isi supernatant and other biological media require neat to appropriate dilution Xi aa CY 8108 T Version 151113 o AO Standard Assay Procedure for Mouse Progranulin j n N oo 10 Mouse Progranulin ELISA Kit L ircuLex User s Manual For Research Use Only Not for use in diagnostic procedures Remove the appropriate number of microtiter wells from the foil pouch and place them ingee well holder Return any unused wells to the foil pouch refold seal with tape and store at 4 C Q 2 Dilute samples with Dilution Buffer See Sample Dilution above 3 Pipette 100 uL of Standard Solutions Std1 Std7 Blank and diluted sample duplicates into the appropriate wells Q 4 Incubate the plate at room temperature ca 25 C for 1 5 hours shakii ca 300 rpm on an orbital microplate shaker RA W Wash 4 times by filling each well with Wash Buffer 350 uL using squirt bottle multi channel pipette manifold dispenser or microplate washer 6 Add 100 uL of HRP conjugated Detection Antibody into each on Incubate the plate at room temperature ca 25 C for Sous shaking at ca 300 rpm on an orbital microplate shaker 2 Wash 4 times by filling each well with Wash Bufeo uL
17. rophage infiltration into omental adipose tissue Diabetes vol 58 pp 627 636 2009 T njes A Fasshauer M Kratzsch J Stumvoll M and M ae dipokine pattern in subjects with impaired fasting glucose and impaired glucose tolerance comparison to normal glucose tolerance and diabetes PLoS One vol 5 no 11 Article ID e139 2010 rs A Q O Q Related Products Q CircuLex Rat Adiponectin ELISA Kit Cat CY 8049 CircuLex Human Adiponectin ELISA Kit Cat 8050 CircuLex Mouse Adiponectin ELISA Kit Cat 8051 CircuLex Dog Adiponectin ELISA Kit Cat CY 8052 CircuLex Human TXNIP ELISA Kit Cat 8090 CircuLex Human Progranulin ELISA Kig at CY 8101 CircuLex Mouse Progranulin ELISA Ke at CY 8108 amp A y X Q PRODUCED BY a wv CycLex Co Ltd oy 1063 103 Terasawa Ina Nagano 396 0002 Japan Fax 81 265 48 7618 ircuLex products are supplied for research use only CycLex CircuLex products and ents thereof may not be resold modified for resale or used to manufacture commercial cts without prior written approval from CycLex Co Ltd To inquire about licensing for commercial use please contact us via email kA at CY 8108 14 Version 1511 o c 13
18. search Use Only Not for use in diagnostic procedures amp Precautions and Recommendations 3 e Allow all the components to come to room temperature before use we e All microplate strips that are not immediately required should be returned to the zip lock Xa which must be carefully resealed to avoid moisture absorption amp e Do not use kit components beyond the indicated kit expiration date e Use only the microtiter wells provided with the kit e Rinse all detergent residues from glassware e Use deionized water of the highest quality e Do not mix reagents from different kits RU S Y A RG N amp The buffers and reagents used in this kit contain NaN3 as presgttives Care should be taken to avoid direct contact with these reagents lt Do not mouth pipette or ingest any of the reagents 4 gt e Do not smoke eat or drink when performing the yay or in areas where samples or reagents are handled andle aS e Dispose of tetra methylbenzidine TMB conge solutions in compliance with local regulations e Avoid contact with the acidic Stop Solutiggspnd Substrate Solution which contains hydrogen peroxide e Wear gloves and eye protection wheg Andling immunodiagnostic materials and samples of mouse origin and these reagents In case ay ntact with the Stop Solution and the Substrate Solution wash skin thoroughly with water and Sey edical attention when necessary e Biological samples may be
19. urine development Dev Dyn 227 593 59Q 6 Mackenzie I R Baker M Pickering Brown S Hsighg G Y Lindholm C Dwosh E Gass J Cannon A Rademakers R Hutton M Feldman HOJ 2006 The neuropathology of frontotemporal lobar degeneration caused by mutations in the A gene Brain 129 3081 3090 7 Matsubara T Mita A Minami K Hosoo Kitazawa S Takahashi K Tamori Y Yokoi N Watanabe M Matsuo E Nishimura O Sejnd S 2012 PGRN is a key adipokine mediating high fat diet induced insulin resistance and obesjtpproush IL 6 in adipose tissue Cell Metab 15 38 50 8 Baker M Mackenzie I R Pickerin Brown S M Gass J Rademakers R Lindholm C Snowden J Adamson J Sadovnick A D llinson S Cannon A Dwosh E Neary D Melquist S Richardson A Dickson D Be Eriksen J Robinson T Zehr C Dickey C A Crook R McGowan E Mann D Boevgp Feldman H Hutton M 2006 Mutations in progranulin cause tau negative rontotemporal Q ntia linked to chromosome 17 Nature 442 916 919 9 Cruts M Gijselinck Ka der Zee J Engelborghs S Wils H Pirici D Rademakers R Vandenberghe R Derntattt B Martin J J van Duijn C Peeters K Sciot R Santens P De Pooter T Mattheijssens M N Nien Broeck M Cuijt I Vennekens K De Deyn P P Kumar Singh S Van Broeckhoven C eG Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked t omosome 17q21 Nature 442
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