{"id":"https://openalex.org/W4389230722","doi":"https://doi.org/10.1182/blood-2023-181881","title":"Genetic Complementation Studies Reveal That Many Disease-Associated DDX41 Variants Do Not Cause Loss of Protein Function","display_name":"Genetic Complementation Studies Reveal That Many Disease-Associated DDX41 Variants Do Not Cause Loss of Protein Function","publication_year":2023,"publication_date":"2023-11-02","ids":{"openalex":"https://openalex.org/W4389230722","doi":"https://doi.org/10.1182/blood-2023-181881"},"language":"en","primary_location":{"id":"doi:10.1182/blood-2023-181881","doi":"https://doi.org/10.1182/blood-2023-181881","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1182/blood-2023-181881","pdf_url":"https://ashpublications.org/blood/article-pdf/142/Supplement 1/4104/2189788/blood-705-main.pdf","source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"},"volume":null,"type":"conference-abstract","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"bronze","oa_url":"https://ashpublications.org/blood/article-pdf/142/Supplement 1/4104/2189788/blood-705-main.pdf","any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5042201153","display_name":"Timothy M. Chlon","orcid":"https://orcid.org/0000-0002-0133-8949","observed_orcids":["https://orcid.org/0000-0002-0133-8949"]},"institutions":[{"id":"https://openalex.org/I1285204247","display_name":"Cincinnati Children's Hospital Medical Center","ror":"https://ror.org/01hcyya48","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1285204247"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Timothy Chlon","raw_affiliation_strings":["1Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, Cincinnati, OH"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, Cincinnati, OH","institution_ids":["https://openalex.org/I1285204247"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5075085570","display_name":"Emily Stepanchick","orcid":"https://orcid.org/0000-0001-6733-3190","observed_orcids":["https://orcid.org/0000-0001-6733-3190"]},"institutions":[{"id":"https://openalex.org/I1285204247","display_name":"Cincinnati Children's Hospital Medical Center","ror":"https://ror.org/01hcyya48","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1285204247"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Emily Stepanchick","raw_affiliation_strings":["1Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, Cincinnati, OH"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, Cincinnati, OH","institution_ids":["https://openalex.org/I1285204247"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5078452873","display_name":"Christy M. Finke","orcid":"https://orcid.org/0009-0006-2843-9025","observed_orcids":["https://orcid.org/0009-0006-2843-9025"]},"institutions":[{"id":"https://openalex.org/I1330342723","display_name":"Mayo Clinic","ror":"https://ror.org/02qp3tb03","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1330342723"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Christy M Finke","raw_affiliation_strings":["2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN","institution_ids":["https://openalex.org/I1330342723"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5006929029","display_name":"Terra L. Lasho","orcid":"https://orcid.org/0000-0002-0315-5230","observed_orcids":["https://orcid.org/0000-0002-0315-5230"]},"institutions":[{"id":"https://openalex.org/I1330342723","display_name":"Mayo Clinic","ror":"https://ror.org/02qp3tb03","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1330342723"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Terra L Lasho","raw_affiliation_strings":["2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN","institution_ids":["https://openalex.org/I1330342723"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5079157559","display_name":"Talha Badar","orcid":"https://orcid.org/0000-0003-1548-918X","observed_orcids":["https://orcid.org/0000-0003-1548-918X"]},"institutions":[{"id":"https://openalex.org/I4210146710","display_name":"Mayo Clinic in Florida","ror":"https://ror.org/03zzw1w08","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1330342723","https://openalex.org/I4210146710"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Talha Badar","raw_affiliation_strings":["3Mayo Clinic, Jacksonville, FL"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"3Mayo Clinic, Jacksonville, FL","institution_ids":["https://openalex.org/I4210146710"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5073698059","display_name":"Alejandro Ferrer","orcid":"https://orcid.org/0000-0002-4883-3023","observed_orcids":["https://orcid.org/0000-0002-4883-3023"]},"institutions":[{"id":"https://openalex.org/I1330342723","display_name":"Mayo Clinic","ror":"https://ror.org/02qp3tb03","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1330342723"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Alejandro Ferrer","raw_affiliation_strings":["4Division of Hematology, Mayo Clinic, Rochester, MN"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"4Division of Hematology, Mayo Clinic, Rochester, MN","institution_ids":["https://openalex.org/I1330342723"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5072463255","display_name":"Mrinal M. Patnaik","orcid":"https://orcid.org/0000-0001-6998-662X","observed_orcids":["https://orcid.org/0000-0001-6998-662X"]},"institutions":[{"id":"https://openalex.org/I1330342723","display_name":"Mayo Clinic","ror":"https://ror.org/02qp3tb03","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1330342723"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Mrinal M. Patnaik","raw_affiliation_strings":["2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN","institution_ids":["https://openalex.org/I1330342723"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":3,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":{"value":5000,"currency":"USD","value_usd":5000},"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":"142","issue":"Supplement 1","first_page":"4104","last_page":"4104"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10309","display_name":"Acute Myeloid Leukemia Research","score":0.9574999809265137,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T10309","display_name":"Acute Myeloid Leukemia Research","score":0.9574999809265137,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11642","display_name":"Genomics and Rare Diseases","score":0.013500000350177288,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T12919","display_name":"Blood disorders and treatments","score":0.005900000222027302,"subfield":{"id":"https://openalex.org/subfields/1311","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/ddx41","display_name":"DDX41","score":0.9890000224113464},{"id":"https://openalex.org/keywords/missense-mutations","display_name":"missense mutations","score":0.7649999856948853},{"id":"https://openalex.org/keywords/variants-of-uncertain-significance","display_name":"variants of uncertain significance","score":0.9739999771118164},{"id":"https://openalex.org/keywords/genetic-complementation","display_name":"gene complementation","score":0.7789999842643738},{"id":"https://openalex.org/keywords/rna-helicase","display_name":"RNA helicase","score":0.8659999966621399},{"id":"https://openalex.org/keywords/myelodysplastic-syndrome","display_name":"myelodysplastic syndrome","score":0.9440000057220459},{"id":"https://openalex.org/keywords/acute-myeloid-leukemia","display_name":"acute myeloid leukemia","score":1.0},{"id":"https://openalex.org/keywords/germline-predisposition","display_name":"germline predisposition","score":0.7950000166893005},{"id":"https://openalex.org/keywords/truncating-variants","display_name":"truncating mutations","score":0.7269999980926514},{"id":"https://openalex.org/keywords/loss-of-function","display_name":"loss of function","score":0.5659999847412109},{"id":"https://openalex.org/keywords/hematopoietic-progenitor-cells","display_name":"hematopoietic progenitor cells","score":0.8920000195503235},{"id":"https://openalex.org/keywords/cell-proliferation-and-survival","display_name":"cell proliferation and survival","score":0.5339999794960022},{"id":"https://openalex.org/keywords/somatic-mutations","display_name":"somatic mutations","score":0.4950000047683716}],"concepts":[{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.6799227595329285},{"id":"https://openalex.org/C75563809","wikidata":"https://www.wikidata.org/wiki/Q2656896","display_name":"Missense mutation","level":4,"score":0.6361405849456787},{"id":"https://openalex.org/C29906990","wikidata":"https://www.wikidata.org/wiki/Q1440688","display_name":"Frameshift mutation","level":4,"score":0.5407557487487793},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.5065044164657593},{"id":"https://openalex.org/C109825262","wikidata":"https://www.wikidata.org/wiki/Q1139164","display_name":"Germline","level":3,"score":0.47604799270629883},{"id":"https://openalex.org/C501734568","wikidata":"https://www.wikidata.org/wiki/Q42918","display_name":"Mutation","level":3,"score":0.4441159665584564},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.42063796520233154},{"id":"https://openalex.org/C13514818","wikidata":"https://www.wikidata.org/wiki/Q5552256","display_name":"Germline mutation","level":4,"score":0.41478171944618225},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.17201825976371765}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1182/blood-2023-181881","doi":"https://doi.org/10.1182/blood-2023-181881","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1182/blood-2023-181881","pdf_url":"https://ashpublications.org/blood/article-pdf/142/Supplement 1/4104/2189788/blood-705-main.pdf","source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"}],"best_oa_location":{"id":"doi:10.1182/blood-2023-181881","doi":"https://doi.org/10.1182/blood-2023-181881","is_oa":true,"landing_page_url":"http://dx.doi.org/10.1182/blood-2023-181881","pdf_url":"https://ashpublications.org/blood/article-pdf/142/Supplement 1/4104/2189788/blood-705-main.pdf","source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"},"sustainable_development_goals":[{"score":0.98580002784729,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"sustainable_development_goals_aurora":[{"score":0.6800000071525574,"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W4389230722.pdf","grobid_xml":"https://content.openalex.org/works/W4389230722.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W4417005966","https://openalex.org/W4417007984","https://openalex.org/W7163048013","https://openalex.org/W4391443032","https://openalex.org/W4405046316","https://openalex.org/W3097130141","https://openalex.org/W3198429224","https://openalex.org/W2990164377","https://openalex.org/W4392667924","https://openalex.org/W4283319893"],"abstract_inverted_index":{"Germline":[0],"variants":[1,38,48,72,80,94,110,151,258,290,301,312,380,485,501,510,538,551],"in":[2,39,115,161,186,261,302,397,417,486,557],"DDX41":[3,21,47,53,71,82,109,144,153,195,228,260,353,370,393,454,484,500,537],"are":[4,73,90,291,409,461,515,552],"the":[5,33,52,67,116,128,138,175,198,208,230,235,240,246,250,268,272,283,295,303,326,333,339,373,376,480,532,542,549],"most":[6,176],"common":[7,177],"cause":[8,49,518,539],"of":[9,36,45,51,59,70,77,95,101,119,143,169,174,193,200,207,226,234,239,259,267,276,297,313,320,352,369,375,384,388,411,431,483,544],"inherited":[10],"predisposition":[11],"to":[12,56,196,244,337,506,517],"Myelodysplastic":[13],"Syndromes":[14],"(MDS)":[15],"and":[16,31,87,121,189,205,217,232,256,264,274,310,323,328,400,433,463,511,560],"Acute":[17],"Myeloid":[18],"Leukemia":[19],"(AML).":[20],"codes":[22],"for":[23,127,287,372,394],"an":[24],"RNA":[25],"helicase":[26],"with":[27,104,166,441,498,508],"many":[28],"described":[29],"functions,":[30],"thus":[32,88,512],"precise":[34,481],"role":[35,482],"these":[37,78,289,474,513,524],"disease":[40,519],"is":[41,84,356,429,471],"uncertain.":[42],"Approximately":[43],"2/3":[44],"disease-associated":[46],"truncation":[50],"protein":[54,470],"due":[55],"frameshift,":[57],"loss":[58,142,351],"a":[60,112,157,184],"translation":[61,359],"start,":[62],"or":[63,107,348,367],"splice":[64],"alterations,":[65],"while":[66,237],"other":[68,117],"1/3":[69],"missense.":[74],"The":[75],"effect":[76,199,296],"missense":[79,108,178,499],"on":[81,203],"function":[83],"largely":[85],"unknown":[86,96],"they":[89],"typically":[91],"categorized":[92],"as":[93],"significance":[97],"(VUSs).":[98],"Importantly,":[99],"30-50%":[100],"MDS/AML":[102,540],"patients":[103,497],"either":[105],"truncating":[106,300,379,509],"acquire":[111],"somatic":[113],"mutation":[114,123,140],"allele":[118],"DDX41,":[120],"this":[122,262,389,545],"has":[124],"strong":[125],"preference":[126],"amino":[129],"acid":[130],"substitution":[131],"R525H.":[132],"Our":[133],"previous":[134],"work":[135],"demonstrated":[136],"that":[137,282,344,358,402,452,496,548],"R525H":[139,241],"causes":[141,350],"function.":[145,354],"To":[146,293],"better":[147],"understand":[148],"how":[149],"germline":[150,550],"affect":[152],"function,":[154],"we":[155,306,316,391],"designed":[156],"genetic":[158],"complementation":[159],"strategy":[160],"immortalized":[162],"hematopoietic":[163],"progenitor":[164],"cells":[165,188,213,278,377,399,419,440],"inducible":[167],"deletion":[168,192],"DDX41.":[170,314],"We":[171,248],"screened":[172,249],"six":[173,266],"VUSs":[179],"by":[180,288,325,378,520,535],"expressing":[181],"them":[182],"from":[183,360,420,457,490],"lentivirus":[185],"DDX41-proficient":[187],"then":[190],"inducing":[191],"endogenous":[194],"determine":[197],"each":[201],"VUS":[202],"proliferation":[204,233,275,322,467],"survival":[206,231,273,324],"cells.":[209,247,340],"Empty":[210],"vector-transduced":[211],"DDX41-deleted":[212,277],"undergo":[214],"cell-cycle":[215],"arrest":[216],"apoptosis":[218],"within":[219],"3-4":[220],"days.":[221],"In":[222,331,386],"contrast,":[223,332],"viral":[224],"expression":[225,238],"wild-type":[227],"rescues":[229],"cells,":[236],"mutant":[242,284],"fails":[243],"rescue":[245,319,338,374],"Y33H,":[251],"M155H,":[252],"G173R,":[253],"R219H,":[254],"P258L,":[255],"I396T":[257],"assay,":[263,305],"all":[265,558],"mutants":[269],"successfully":[270],"rescued":[271],"long-term.":[279],"This":[280,449],"indicates":[281,451,495],"proteins":[285],"coded":[286],"functional.":[292],"test":[294],"commonly":[298],"observed":[299],"same":[304],"expressed":[307,456],"M1I,":[308],"Q52fs,":[309],"D140Gfs":[311,334],"Surprisingly,":[315],"saw":[317],"complete":[318,554],"cell":[321,466,525],"M1I":[327],"Q52fs":[329],"variants.":[330],"variant":[335],"failed":[336],"These":[341],"data":[342,475],"indicate":[343],"frameshift":[345,415,443],"at":[346,365],"D140":[347],"later":[349],"It":[355],"likely":[357],"alternative":[361,458],"methionine":[362],"residues":[363],"located":[364],"M127":[366,432],"M132":[368],"accounts":[371],"affecting":[381],"sites":[382,460],"upstream":[383,410],"M127.":[385],"support":[387,465],"theory,":[390],"targeted":[392],"CRISPR-mediated":[395],"knockout":[396],"MOLM13":[398],"found":[401],"guide":[403],"RNAs":[404],"targeting":[405,425],"exons":[406],"1-4,":[407],"which":[408,428,536],"M127,":[412],"produced":[413],"homozygous":[414,442],"mutations":[416],"proliferating":[418],"single-cell":[421],"clones.":[422,448],"However,":[423],"guides":[424],"exon":[426],"6,":[427],"downstream":[430],"M132,":[434],"did":[435],"not":[436,529,553],"produce":[437],"any":[438],"surviving":[439],"mutations,":[444],"despite":[445],"screening":[446],"96":[447],"finding":[450],"short":[453],"isoforms":[455],"start":[459],"functional":[462],"can":[464],"when":[468],"full-length":[469],"lost.":[472],"Collectively,":[473],"raise":[476],"important":[477],"questions":[478],"about":[479],"hematologic":[487],"malignancy.":[488],"Data":[489],"recently":[491],"published":[492],"patient":[493,504],"cohorts":[494],"have":[502],"similar":[503,521],"characteristics":[505],"those":[507],"aberrations":[514],"thought":[516],"mechanisms.":[522],"While":[523],"line":[526],"models":[527],"may":[528,564],"fully":[530],"recapitulate":[531],"pathogenic":[533],"mechanism":[534],"predisposition,":[541],"results":[543],"study":[546],"demonstrate":[547],"loss-of-function":[555],"alleles":[556],"cases":[559],"more":[561],"complex":[562],"mechanisms":[563],"be":[565],"involved.":[566]},"counts_by_year":[],"updated_date":"2026-08-28T12:50:07.497085","created_date":"2023-12-02T00:00:00"}