{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T17:54:14Z","timestamp":1761933254691,"version":"build-2065373602"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017540","name":"NHLBI Division of Intramural Research","doi-asserted-by":"publisher","award":["U42oD011140"],"award-info":[{"award-number":["U42oD011140"]}],"id":[{"id":"10.13039\/100017540","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002086","name":"Fanconi Anemia Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002086","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Although small animal models of Fanconi anemia (FA) are useful, they do not faithfully replicate many of the clinical features seen in FA patients. We reasoned that a porcine model of FA with its similar physiology and a relatively long lifespan would produce a phenotype more similar to human FA. Targeting\n                    <jats:italic>FANCA<\/jats:italic>\n                    in domestic swine resulted in skeletal abnormalities and extreme sensitivity to interstrand DNA cross-linking agents. In addition, FANCA disruption followed by mitomycin C treatment resulted in a\u2009&gt;\u200910-fold increase in chromosomal radials, a finding that is considered diagnostic for human FA. Bone marrow derived, hematopoietic progenitor cells from a FANCA null pig showed a 75% reduction in colony forming activity compared to wild type. Evaluation of steady state hematopoiesis in the peripheral blood revealed the gradual development of red cell macrocytosis and a reduction in circulating neutrophils. Targeting of\n                    <jats:italic>FANCD2<\/jats:italic>\n                    failed to produce any biallelic animals demonstrating the loss of FANCD2 function is embryonic lethal in pigs. These results indicate that a porcine model of FANCA holds promise for the development of strategies to prevent the development of bone marrow failure and malignancies in patients with FA.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0335854","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T17:51:16Z","timestamp":1761933076000},"page":"e0335854","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A porcine model of Fanconi anemia"],"prefix":"10.1371","volume":"20","author":[{"given":"Brandon","family":"Hergert","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin M.","family":"Whitworth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devorah C.","family":"Goldman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey","family":"McQueen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalindi","family":"Parmar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"D\u2019Andrea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa S.","family":"Samuel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin D.","family":"Wells","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Randall S.","family":"Prather","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig","family":"Dorell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Grompe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William H.","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"issue":"18","key":"pone.0335854.ref001","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1182\/blood-2014-04-526293","article-title":"Stress and DNA repair biology of the Fanconi anemia pathway","volume":"124","author":"S Longerich","year":"2014","journal-title":"Blood"},{"key":"pone.0335854.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.dnarep.2018.02.003","article-title":"Inhibition of non-homologous end joining in Fanconi Anemia cells results in rescue of survival after interstrand crosslinks but sensitization to replication associated double-strand breaks","volume":"64","author":"LJ Eccles","year":"2018","journal-title":"DNA Repair (Amst)"},{"key":"pone.0335854.ref003","doi-asserted-by":"crossref","first-page":"100589","DOI":"10.1016\/j.blre.2019.100589","article-title":"Genotype-phenotype associations in Fanconi anemia: A literature review","volume":"37","author":"MO Fiesco-Roa","year":"2019","journal-title":"Blood Rev"},{"key":"pone.0335854.ref004","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1159\/000346035","article-title":"VACTERL-H Association and Fanconi Anemia","volume":"4","author":"BP Alter","year":"2013","journal-title":"Mol Syndromol"},{"issue":"1","key":"pone.0335854.ref005","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1182\/blood-2013-09-427740","article-title":"Why does the bone marrow fail in Fanconi anemia?","volume":"123","author":"JI Garaycoechea","year":"2014","journal-title":"Blood"},{"key":"pone.0335854.ref006","doi-asserted-by":"crossref","first-page":"104816","DOI":"10.1016\/j.oraloncology.2020.104816","article-title":"Management of Fanconi Anemia patients with head and neck carcinoma: Diagnosis and treatment adaptation","volume":"108","author":"A Beddok","year":"2020","journal-title":"Oral Oncol"},{"key":"pone.0335854.ref007","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.semcdb.2020.11.010","article-title":"Animal models of Fanconi anemia: A developmental and therapeutic perspective on a multifaceted disease","volume":"113","author":"L Guitton-Sert","year":"2021","journal-title":"Semin Cell Dev Biol"},{"key":"pone.0335854.ref008","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.mrfmmm.2009.03.015","article-title":"Mouse models of Fanconi anemia","volume":"668","author":"K Parmar","year":"2009","journal-title":"Mutat Res"},{"issue":"8","key":"pone.0335854.ref009","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1097\/MPH.0b013e3181e8865f","article-title":"Chromosomal breakage study in children suspected with Fanconi anemia in the Indian population","volume":"32","author":"S Korgaonkar","year":"2010","journal-title":"J Pediatr Hematol Oncol"},{"issue":"5","key":"pone.0335854.ref010","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.stemcr.2018.10.001","article-title":"Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia","volume":"11","author":"C Domenech","year":"2018","journal-title":"Stem Cell Reports"},{"issue":"5","key":"pone.0335854.ref011","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.stemcr.2016.09.005","article-title":"Endogenous DNA Damage Leads to p53-Independent Deficits in Replicative Fitness in Fetal Murine Fancd2-\/- Hematopoietic Stem and Progenitor Cells","volume":"7","author":"YM Yoon","year":"2016","journal-title":"Stem Cell Reports"},{"issue":"11","key":"pone.0335854.ref012","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1182\/blood-2012-06-439679","article-title":"Fetal origins of hematopoietic failure in a murine model of Fanconi anemia","volume":"121","author":"AN Kamimae-Lanning","year":"2013","journal-title":"Blood"},{"key":"pone.0335854.ref013","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev.med.53.082901.103900","article-title":"Will the pig solve the transplantation backlog?","volume":"53","author":"DKC Cooper","year":"2002","journal-title":"Annu Rev Med"},{"issue":"6","key":"pone.0335854.ref014","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/s41374-018-0026-7","article-title":"Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs","volume":"98","author":"DK Meyerholz","year":"2018","journal-title":"Lab Invest"},{"issue":"2","key":"pone.0335854.ref015","doi-asserted-by":"crossref","first-page":"488","DOI":"10.3390\/ijms21020488","article-title":"Genetically Engineered Pigs to Study Cancer","volume":"21","author":"D Kalla","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"29","key":"pone.0335854.ref016","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1703998114","article-title":"Quadrupling efficiency in production of genetically modified pigs through improved oocyte maturation","volume":"114","author":"Y Yuan","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0335854.ref017","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-1-4939-9566-0_6","article-title":"In Vitro Maturation, Fertilization, and Culture of Pig Oocytes and Embryos","volume":"2006","author":"BK Redel","year":"2019","journal-title":"Methods Mol Biol"},{"issue":"3","key":"pone.0335854.ref018","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1095\/biolreprod.114.121723","article-title":"Use of the CRISPR\/Cas9 system to produce genetically engineered pigs from in vitro-derived oocytes and embryos","volume":"91","author":"KM Whitworth","year":"2014","journal-title":"Biol Reprod"},{"issue":"11","key":"pone.0335854.ref019","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1038\/nprot.2013.143","article-title":"Genome engineering using the CRISPR-Cas9 system","volume":"8","author":"FA Ran","year":"2013","journal-title":"Nat Protoc"},{"issue":"1","key":"pone.0335854.ref020","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11248-016-9989-6","article-title":"Zygote injection of CRISPR\/Cas9 RNA successfully modifies the target gene without delaying blastocyst development or altering the sex ratio in pigs","volume":"26","author":"KM Whitworth","year":"2017","journal-title":"Transgenic Res"},{"key":"pone.0335854.ref021","article-title":"Diagnosis of Fanconi anemia by diepoxybutane analysis","volume":"85","author":"AD Auerbach","year":"2015","journal-title":"Curr Protoc Hum Genet"},{"key":"pone.0335854.ref022","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bbrc.2020.11.038","article-title":"Low-temperature incubation improves both knock-in and knock-down efficiencies by the CRISPR\/Cas9 system in Xenopus laevis as revealed by quantitative analysis","volume":"543","author":"S Kato","year":"2021","journal-title":"Biochem Biophys Res Commun"},{"issue":"8","key":"pone.0335854.ref023","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.bjps.2012.02.015","article-title":"Fanconi\u2019s anaemia and unilateral thumb polydactyly--don\u2019t miss it","volume":"65","author":"DJ Wilks","year":"2012","journal-title":"J Plast Reconstr Aesthet Surg"},{"key":"pone.0335854.ref024","first-page":"15","article-title":"Current insights into the diagnosis and treatment of inherited bone marrow failure syndromes in China","volume":"2","author":"X Zhu","year":"2015","journal-title":"Stem Cell Investig"},{"issue":"22","key":"pone.0335854.ref025","doi-asserted-by":"crossref","first-page":"4360","DOI":"10.1128\/MCB.00870-13","article-title":"Inactivation of Uaf1 causes defective homologous recombination and early embryonic lethality in mice","volume":"33","author":"E Park","year":"2013","journal-title":"Mol Cell Biol"},{"issue":"8","key":"pone.0335854.ref026","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1038\/ng.2347","article-title":"FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair","volume":"44","author":"W Zhou","year":"2012","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0335854.ref027","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.devcel.2009.01.001","article-title":"Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype","volume":"16","author":"JM Kim","year":"2009","journal-title":"Dev Cell"},{"issue":"12","key":"pone.0335854.ref028","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1002\/mrd.21242","article-title":"Somatic cell nuclear transfer efficiency: how can it be improved through nuclear remodeling and reprogramming?","volume":"77","author":"KM Whitworth","year":"2010","journal-title":"Mol Reprod Dev"},{"issue":"3","key":"pone.0335854.ref029","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.bbrc.2019.04.201","article-title":"Severe Fanconi Anemia phenotypes in Fancd2 depletion mice","volume":"514","author":"Q Yang","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"issue":"23","key":"pone.0335854.ref030","doi-asserted-by":"crossref","first-page":"9703","DOI":"10.1158\/0008-5472.CAN-09-1022","article-title":"Genomic instability in mice is greater in Fanconi anemia caused by deficiency of Fancd2 than Fancg","volume":"70","author":"R Reliene","year":"2010","journal-title":"Cancer Res"},{"issue":"12","key":"pone.0335854.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1007821","article-title":"Multiplexed CRISPR\/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility","volume":"14","author":"R Ramanagoudr-Bhojappa","year":"2018","journal-title":"PLoS Genet"},{"issue":"16","key":"pone.0335854.ref032","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1101\/gad.1103403","article-title":"Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice","volume":"17","author":"S Houghtaling","year":"2003","journal-title":"Genes Dev"},{"issue":"5","key":"pone.0335854.ref033","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1086\/517616","article-title":"Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype","volume":"80","author":"R Kalb","year":"2007","journal-title":"Am J Hum Genet"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0335854","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T17:51:22Z","timestamp":1761933082000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0335854"}},"subtitle":[],"editor":[{"given":"Younghoon","family":"Kee","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,10,31]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0335854","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,31]]}}}