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Nonsense‐mediated mRNA decay efficiency influences bleeding severity in ITGA2B c. 2659C > T (p. Q887X ) knock‐in mice
Author(s) -
Xie Zhanli,
Jiang Jiang,
Cao Lijuan,
Jiang Miao,
Yang Fei,
Ma Zhenni,
Wang Zhaoyue,
Ruan Changgeng,
Liu Hong,
Zhou Lu
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13975
Subject(s) - nonsense mediated decay , bleeding time , microbiology and biotechnology , biology , gene , genetics , immunology , platelet , platelet aggregation , rna , rna splicing
Glanzmann's thrombasthenia (GT) is a severe hemorrhagic disease. It is caused by mutations in ITGA2B or ITGB3 , which are the respective genes encoding integrin αIIb and β3. Despite widespread mutational analysis, the mechanisms underlying the extensive variability in bleeding severity observed among affected individuals remains poorly understood. In order to explore the mechanisms conferring for bleeding heterogeneity, three GT patients with ITGA2B c.2671C > T (p.Q891X) who possessed different bleeding scores were studied. Analysis showed that there was significant difference in nonsense‐mediated mRNA decay (NMD) efficiency among the three patients. These differences positively correlated with their bleeding score. Next, a knock‐in mouse model (KI mice) with the ITGA2B c.2659C > T (p.Q887X) was generated using CRISPR/Cas9. Importantly, this mutation is homologous to ITGA2B c.2671C > T (p.Q891X) in humans. The bleeding time of KI mice was significantly in comparison to the wide‐type mice. Interestingly, bleeding was stopped after treatment with caffeine, which is a known NMD inhibitor. This suggests that NMD efficiency potentially influences bleeding severity in ITGA2B c.2659C > T (p.Q887X) KI mice.