{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T18:30:14Z","timestamp":1781029814200,"version":"3.54.1"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":46,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1ZIACL090052"],"award-info":[{"award-number":["1ZIACL090052"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1ZIACL090053"],"award-info":[{"award-number":["1ZIACL090053"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1ZIACL090054"],"award-info":[{"award-number":["1ZIACL090054"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,23]]},"abstract":"<jats:p>\n                    Growing evidence indicates that\n                    <jats:italic>PKLR<\/jats:italic>\n                    , the gene for pyruvate kinase (PK), is a genetic modifier of the sickle cell phenotype. Coinheritance of specific\n                    <jats:italic>PKLR<\/jats:italic>\n                    variants is associated with increased pain-related hospitalization and can trigger sickle cell disease (SCD) phenotypes in asymptomatic carriers. PK deficiency disrupts RBC glycolysis, leading to ATP deficits and accumulation of 2,3-diphosphoglycerate, which exacerbates sickling in SCD. Using CRISPR-Cas9, we generated null mutations in\n                    <jats:italic>Pklr<\/jats:italic>\n                    [\n                    <jats:italic>\n                      Pklr\n                      <jats:sup>(13ntdel\/13ntdel)<\/jats:sup>\n                    <\/jats:italic>\n                    or\n                    <jats:italic>\n                      Pklr\n                      <jats:sup>(246ntdel\/246ntdel)<\/jats:sup>\n                    <\/jats:italic>\n                    ] specific for the RBC isoform (PKR) in Townes mice that were homozygous (SS) or heterozygous (AS) for the human sickle globin gene, or homozygous for human hemoglobin A (AA, controls), to investigate the effect of PKR deficiency on the sickle phenotype in mice. PKR-deficient AA and AS mice developed severe anemia, reticulocytosis, and substantial spleen and liver iron deposits. Unlike what is observed in humans, PKR deficiency in AS and SS mice surprisingly decreased sickling, but it was also associated with increased extramedullary hematopoiesis and mitochondrial retention in mature RBCs. These results demonstrate the differential effect of\n                    <jats:italic>Pklr<\/jats:italic>\n                    mutations on the phenotype of both AS and SS mouse models, offering insights into the complex role of PKR deficiency in SCD pathology.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.195682","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T17:45:57Z","timestamp":1768931157000},"source":"Crossref","is-referenced-by-count":2,"title":["Pyruvate kinase deficiency modifies sickle hemoglobin carrier and sickle cell disease phenotypes in mice"],"prefix":"10.1172","volume":"11","author":[{"given":"Xunde","family":"Wang","sequence":"first","affiliation":[{"name":"Sickle Cell Branch, National Heart Lung and Blood Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghann","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Perioperative Medicine, National Institutes of 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