{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T10:26:55Z","timestamp":1762252015240},"reference-count":30,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T00:00:00Z","timestamp":1393804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:p>Red blood cell pyruvate kinase (PK\u2010R) is a key regulatory enzyme of red cell metabolism. Hereditary deficiency of PK\u2010R is caused by mutations in the <jats:italic>PKLR<\/jats:italic> gene, leading to chronic nonspherocytic hemolytic anemia. In contrast to PK deficiency, inherited PK hyperactivity has also been described. This very rare abnormality of RBC metabolism has been documented in only two families and appears to be without clinical consequences. Thus far, it has been attributed to either a gain of function mutation in <jats:italic>PKLR<\/jats:italic> or to persistent expression of the fetal PK isozyme PK\u2010M2 in mature red blood cells. We here report on a novel type of inherited PK hyperactivity that is characterized by solely increased expression of a kinetically normal PK\u2010R. In line with the latter, no mutations were detected in <jats:italic>PKLR<\/jats:italic>. Mutations in regulatory regions as well as variations in <jats:italic>PKLR<\/jats:italic> copy number were also absent. In addition, linkage analysis suggested that PK hyperactivity segregated independently from the <jats:italic>PKLR<\/jats:italic> locus. We therefore postulate that the causative mutation resides in a novel yet\u2010unidentified locus, and upregulates <jats:italic>PKLR<\/jats:italic> gene expression. Other mutations of the same locus may be involved in those cases of PK deficiency that fail to reveal mutations in <jats:italic>PKLR<\/jats:italic>. Am. J. Hematol. 89:380\u2013384, 2014. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.23647","type":"journal-article","created":{"date-parts":[[2013,12,4]],"date-time":"2013-12-04T13:13:15Z","timestamp":1386162795000},"page":"380-384","source":"Crossref","is-referenced-by-count":7,"title":["Novel type of red blood cell pyruvate kinase hyperactivity predicts a remote regulatory locus involved in <i>PKLR<\/i> gene expression"],"prefix":"10.1002","volume":"89","author":[{"given":"Brigitte Antoinette","family":"van Oirschot","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerney Johanna Jeanette Maria","family":"Francois","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wouter Willem","family":"van Solinge","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annet Cornelia Wilhelmina","family":"van Wesel","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gert","family":"Rijksen","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans Kristian Ploos","family":"van Amstel","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"van Wijk","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,3,3]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1622"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05520.x"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.12328"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07535.x"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.11.3585"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.7754\/Clin.Lab.2012.120905"},{"key":"e_1_2_5_8_1","first-page":"366","article-title":"Hereditary high ATP content of human erythrocytes","volume":"83","author":"Zurcher C","year":"1965","journal-title":"Folia Haematol Int Mag Klin Morphol Blutforsch"},{"key":"e_1_2_5_9_1","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1182\/blood.V56.5.902.902","article-title":"Pyruvate kinase hyperactivity genetically determined: metabolic consequences and molecular characterization","volume":"56","author":"Max\u2010Audit I","year":"1980","journal-title":"Blood"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111406"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1997)9:3<282::AID-HUMU13>3.0.CO;2-Z"},{"key":"e_1_2_5_12_1","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1182\/blood.V64.4.930.930","article-title":"Pattern of pyruvate kinase isozymes in erythroleukemia cell lines and in normal human erythroblasts","volume":"64","author":"Max\u2010Audit I","year":"1984","journal-title":"Blood"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.2830100108"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20915"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001046"},{"key":"e_1_2_5_16_1","first-page":"188","volume-title":"Red cell metabolism. 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