An ENU-induced recessive mutation in Mpl leads to thrombocytopenia with overdominance.
An ENU-induced recessive mutation in Mpl leads to thrombocytopenia with overdominance.
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DOI：
10.1016/j.exphem.2008.10.005
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发表时间：
2009-02
影响因子：
2.6
通讯作者：
Adams, Mark D.
中科院分区：
文献类型：
--
作者：
Chan, E. Ricky;Lavender, Heather;Li, Geqiang;Haviernik, Peter;Bunting, Kevin D.;Adams, Mark D.
这项研究的目的是鉴定和表征在杰克逊实验室作为大规模enu突变筛选的一部分产生的血小板减少小鼠品系HLB219的致病突变。通过将HLB219与BALB/cByJ （BALB）和129/SvImJ （129/Sv）杂交产生的F2小鼠进行区间定位，鉴定出HLB219突变。Mpl被确定为候选基因并测序。该突变在小鼠造血干细胞/祖细胞实验和细胞培养中通过Ba/F3细胞的表达得到了表征。HLB219小鼠血小板生成素（TPO）受体Mpl的新突变导致该受体胞外区密码子40的Cys→Arg替换。与野生型C57BL/6J菌株相比，Mplhlb219突变纯合子小鼠的血小板数量减少80%，骨髓巨核细胞数量减少，TPO水平高，竞争性繁殖能力下降，与受体功能缺失突变一致。而Mplhlb219杂合的小鼠则表现出显性效应，血小板数量显著增加。体外功能分析表明，表达突变体MPLhlb219蛋白的Ba/F3细胞不能激活ERK和STAT5，但在缺乏TPO的情况下增殖，并且需要AKT的组成磷酸化才能进行细胞因子独立生长。HLB219小鼠的血小板减少症是由Mpl的隐性突变引起的，该突变可消除MAPK-ERK和JAK-STAT信号。
The aim of this study was to identify and characterize the causative mutation in the thrombocytopenic mouse strain HLB219 that was generated at the Jackson Laboratory as part of a large scale ENU-mutagenesis screen. The HLB219 mutation was identified by interval mapping of F2 mice generated from intercross breeding of HLB219 to both BALB/cByJ (BALB) and 129/SvImJ (129/Sv). Mpl was identified as a candidate gene and sequenced. The mutation was characterized in vivo in mouse hematopoietic stem/progenitor cell assays and in cell culture by expression in Ba/F3 cells. A novel mutation in the thrombopoietin (TPO) receptor Mpl in HLB219 mice caused a Cys→Arg substitution at codon 40 in the extracellular region of the receptor. Mice homozygous for the Mplhlb219 mutation had an 80% decrease in the number of platelets in comparison to the wild type C57BL/6J strain, low numbers of bone marrow megakaryocytes, high TPO levels, and decreased competitive repopulating ability, consistent with a loss-of-function mutation in the receptor. Mice heterozygous for Mplhlb219 however, showed an overdominance effect with a significant increase in platelet number. Functional analysis in vitro demonstrated that Ba/F3 cells expressing the mutant MPLhlb219 protein failed to activate ERK and STAT5, but proliferated in the absence of TPO and required constitutive phosphorylation of AKT for cytokine-independent growth. Thrombocytopenia in HLB219 mice is caused by a recessive mutation in Mpl that abrogates MAPK-ERK and JAK-STAT signaling.
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影响因子：
15.8
作者：
Pikman, Yana;Lee, Benjamin H.;Mercher, Thomas;McDowell, Elizabeth;Ebert, Benjamin L.;Gozo, Maricel;Cuker, Adam;Wernig, Gerlinde;Moore, Sandra;Galinsky, Ilene;DeAngelo, Daniel J.;Clark, Jennifer J.;Lee, Stephanie J.;Golub, Todd R.;Wadleigh, Martha;Gilliland, D. Gary;Levine, Ross L.
通讯作者：
Levine, Ross L.
影响因子：
64.5
作者：
Mason, Kylie D.;Carpinelli, Marina R.;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
影响因子：
64.8
作者：
DESAUVAGE, FJ;HASS, PE;EATON, DL
通讯作者：
EATON, DL
DOI：
10.1073/pnas.0404241101
发表时间：
2004-08-03
影响因子：
11.1
作者：
Moliterno, AR;Williams, DM;Spivak, JL
通讯作者：
Spivak, JL
DOI：
10.1196/annals.1349.018
发表时间：
2005-01-01
期刊：
HEMATOPOIETIC STEM CELLS V
影响因子：
--
作者：
Kaushansky, K
通讯作者：
Kaushansky, K