Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A
Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A
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DOI：
10.1182/blood-2011-06-358853
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发表时间：
2012-01-05
期刊：
影响因子：
20.3
通讯作者：
Adelstein, Robert S.
中科院分区：
文献类型：
--
作者：
Zhang, Yingfan;Conti, Mary Anne;Adelstein, Robert S.
我们已经产生了3个小鼠品系，每个品系在非肌肉肌球蛋白II-A基因Myh 9（R702 C、D1424 N和E1841 K）中具有不同的突变。每一个细胞系都发展出与人类患者相似的MYH 9相关疾病。在Myh 9基因的第一个编码外显子上引入与绿色荧光蛋白融合的R702 C突变体人cDNA，并在相应的外显子上直接引入D1424 N和E1841 K突变。纯合子R702 C小鼠在胚胎第10.5-11.5天死亡，而纯合子D1424 N和E1841 K小鼠存活。所有杂合子和纯合子突变小鼠均表现出巨血小板减少症伴出血时间延长、凝块收缩缺陷和髓外巨核细胞增加。对骨髓中培养的巨核细胞和巨核细胞的活细胞成像的研究表明，杂合R702 C巨核细胞形成较少且较短的前血小板，具有较少的分支和较大的芽。结果表明，破坏的前血小板形成有助于在小鼠和最有可能在人类的巨血小板减少症。我们还观察到过早的白内障形成，肾脏异常，包括蛋白尿，局灶节段性肾小球硬化和进行性肾脏疾病，以及轻度听力损失。我们的研究结果表明，在肌球蛋白运动或补体形成域突变的杂合子小鼠表现出类似的血液学，眼睛和肾脏表型与人类MYH 9相关疾病。（血。2012; 119（1）：238-250）
We have generated 3 mouse lines, each with a different mutation in the nonmuscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9- related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease. (Blood. 2012; 119(1): 238-250)