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ENU 诱变在功能丧失性 Jak2 等位基因中鉴定出一种新型血小板表型。

Enu mutagenesis identifies a novel platelet phenotype in a loss-of-function Jak2 allele.

机构信息

Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

出版信息

PLoS One. 2013 Sep 25;8(9):e75472. doi: 10.1371/journal.pone.0075472. eCollection 2013.

DOI:10.1371/journal.pone.0075472
PMID:24086539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3783367/
Abstract

Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2(K915X)), resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2(+/-)). Timed pregnancy experiments revealed that Jak2(K915X/K915X) and Jak2(-/-) displayed embryonic lethality; however, Jak2(K915X/K915X) embryos were viable an additional two days compared to Jak2(-/-) embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.

摘要

利用ENU 诱变，我们鉴定出一种血小板升高的突变鼠。遗传定位将突变定位到编码 Jak2 酪氨酸激酶的染色体 19 上的一个区间。我们鉴定出一个 A3056T 突变，导致 Jak2 第 19 外显子中的一个提前终止密码子（Jak2(K915X)），导致蛋白截断和功能失活酶。在携带 Jak2 基因座（Jak2(+/-)）半合子靶向缺失的小鼠中也观察到这种新型血小板表型。定时妊娠实验表明，Jak2(K915X/K915X)和 Jak2(-/-)显示胚胎致死性；然而，与 Jak2(-/-)胚胎相比，Jak2(K915X/K915X)胚胎的存活时间额外延长了两天。我们的数据表明，扰乱 JAK2 激活可能会对血小板数量的升高产生意想不到的后果，相应地，对用组成性 Jak2 活性治疗血液疾病具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/6f5dabb6a9f5/pone.0075472.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/8ca021b70b56/pone.0075472.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/e3af48008d9a/pone.0075472.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/6f5dabb6a9f5/pone.0075472.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/8ca021b70b56/pone.0075472.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/e3af48008d9a/pone.0075472.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb4/3783367/6f5dabb6a9f5/pone.0075472.g003.jpg

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