{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:55:00Z","timestamp":1777092900097,"version":"3.51.4"},"reference-count":19,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T00:00:00Z","timestamp":1688860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870148"],"award-info":[{"award-number":["81870148"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Haemoglobin H (Hb H) disease (intermediate status of \u03b1\u2010thalassemia) shows marked phenotypic variability from asymptomatic to severe anaemia. Apart from the combined \u03b2\u2010thalassemia allele ameliorating clinical severity, reports of genetic modifier genes affecting the phenotype of Hb H disease are scarce which bring inconvenience to precise diagnosis and genetic counselling of the patients. Here, we present a novel mutation (c.948C&gt;A, p.S316R) in the <jats:italic>PIP4K2A<\/jats:italic> gene in a female Hb H disease patient who displayed moderate anaemia and a relatively high Hb H level. Haematological analysis in her family members revealed that individuals carrying this mutation have upregulated \u03b2\u2010globin expression, leading to a more imbalanced \u03b2\/\u03b1\u2010globin ratio and more Hb H inclusion bodies in peripheral red blood cells. According to functional experiments, the mutant PIP4K2A protein exhibits enhanced protein stability, increased kinase activity and a stronger regulatory effect on downstream proteins, suggesting a gain\u2010of\u2010function mutation. Moreover, introduction of the S316R mutation into HUDEP\u20102 cells increased expression of \u03b2\u2010globin, further inhibiting erythroid differentiation and terminal enucleation. Thus, the S316R mutation is a novel genetic factor associated with \u03b2\u2010globin expression, and the <jats:italic>PIP4K2A<\/jats:italic> gene is a new potential modifier gene affecting the \u03b1\u2010thalassemia phenotype.<\/jats:p>","DOI":"10.1111\/bjh.18967","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T02:49:55Z","timestamp":1688957395000},"page":"1018-1023","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel gain\u2010of\u2010function <scp><i>PIP4K2A<\/i><\/scp> mutation elevates the expression of \u03b2\u2010globin and aggravates the severity of \u03b1\u2010thalassemia"],"prefix":"10.1111","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1052-8602","authenticated-orcid":false,"given":"Yanxia","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongting","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guanxia","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunrong","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Yulin Women and Children Health Care Hospital  Yulin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaofeng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sisi","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Yulin Women and Children Health Care Hospital  Yulin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Yulin Women and Children Health Care Hospital  Yulin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiongda","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Yulin Women and Children Health Care Hospital  Yulin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zezhang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-954X","authenticated-orcid":false,"given":"Dina","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7094-159X","authenticated-orcid":false,"given":"Jiaqiong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-6165","authenticated-orcid":false,"given":"Fu","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"},{"name":"Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1358-0879","authenticated-orcid":false,"given":"Xuan","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, School of Basic Medical Sciences Southern Medical University  Guangzhou China"},{"name":"Innovation Center for Diagnostics and Treatment of Thalassemia, Nanfang Hospital Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,7,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-07-1975"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1013338"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2009.1.26"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1010174"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2016.10.012"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200281"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-020-01107-w"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.77"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20172170"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2009.01325.x"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12443"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.08.015"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-009-1621-5"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-2054-y"},{"issue":"6","key":"e_1_2_11_16_1","first-page":"612","article-title":"Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke","volume":"13","author":"Sacks D","year":"2018","journal-title":"Int J Stroke"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.02.005"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2013.02.001"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.631281"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01337-X"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.18967","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T01:11:27Z","timestamp":1697418687000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.18967"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,9]]},"references-count":19,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1111\/bjh.18967"],"URL":"https:\/\/doi.org\/10.1111\/bjh.18967","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,9]]},"assertion":[{"value":"2023-03-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}