Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability.
Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability.
复制标题
DOI：
10.1371/journal.pone.0071187
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Matsushita T
中科院分区：
文献类型：
--
作者：
Suzuki N;Kunishima S;Ikejiri M;Maruyama S;Sone M;Takagi A;Ikawa M;Okabe M;Kojima T;Saito H;Naoe T;Matsushita T
由MYH 9编码的非肌肉肌球蛋白重链IIA（NMMHCIIA）与称为MYH 9疾病的常染色体显性遗传疾病相关。MYH 9病症的特征在于巨血小板减少症和粒细胞中非常特征性的包涵体。MYH 9疾病经常引起肾炎、感觉神经性听力障碍和白内障。引起这些疾病的最常见和有害的突变之一是R702 C错义突变。我们产生了表达Myh 9 R702 C突变的敲入小鼠。R702 C基因敲入异种小鼠（R702 C +/−小鼠）显示巨血小板减少症。我们研究了培养的R702 C +/−小鼠胎肝细胞的巨核细胞生成，发现前血小板形成受损：前血小板尖端数量减少，前血小板大小增加，前血小板轴变短变大。尽管May-Grünwald Giemsa染色未观察到粒细胞包涵体，但免疫荧光分析表明NMMHCIIA蛋白聚集并积聚在粒细胞胞质中。在其他器官中，R702 C +/−小鼠显示白蛋白尿，随着年龄的增长而增加。肾脏病理检查显示肾小球硬化。感觉性听力损失表现为听性脑干反应降低。这些发现表明，Myh 9 R702 C敲入小鼠反映了由R702 C突变引起的人类MYH 9疾病的特征。
Nonmuscle myosin heavy chain IIA (NMMHCIIA) encoded by MYH9 is associated with autosomal dominantly inherited diseases called MYH9 disorders. MYH9 disorders are characterized by macrothrombocytopenia and very characteristic inclusion bodies in granulocytes. MYH9 disorders frequently cause nephritis, sensorineural hearing disability and cataracts. One of the most common and deleterious mutations causing these disorders is the R702C missense mutation. We generated knock-in mice expressing the Myh9 R702C mutation. R702C knock-in hetero mice (R702C+/− mice) showed macrothrombocytopenia. We studied megakaryopoiesis of cultured fetal liver cells of R702C+/− mice and found that proplatelet formation was impaired: the number of proplatelet tips was decreased, proplatelet size was increased, and proplatelet shafts were short and enlarged. Although granulocyte inclusion bodies were not visible by May–Grünwald Giemsa staining, immunofluorescence analysis indicated that NMMHCIIA proteins aggregated and accumulated in the granulocyte cytoplasm. In other organs, R702C+/− mice displayed albuminuria which increased with age. Renal pathology examination revealed glomerulosclerosis. Sensory hearing loss was indicated by lowered auditory brainstem response. These findings indicate that Myh9 R702C knock-in mice mirror features of human MYH9 disorders arising from the R702C mutation.
登录
查看更多内容
影响因子：
20.3
作者：
Zhang, Yingfan;Conti, Mary Anne;Adelstein, Robert S.
通讯作者：
Adelstein, Robert S.
DOI：
10.1016/j.bbrc.2004.10.147
发表时间：
2004-12-24
影响因子：
3.1
作者：
Matsushita, T;Hayashi, H;Saito, H
通讯作者：
Saito, H
影响因子：
19.6
作者：
Sekine, Takashi;Konno, Mutsuko;Kunishima, Shinji
通讯作者：
Kunishima, Shinji
影响因子：
4.8
作者：
Conti, MA;Even-Ram, S;Adelstein, RS
通讯作者：
Adelstein, RS
影响因子：
30.8
作者：
Kelley, MJ;Jawien, W;Korczak, JF
通讯作者：
Korczak, JF