Elucidation of the mechanisms of giant platelet production in MYH9 disorders

阐明 MYH9 疾病中巨血小板产生的机制

• 批准号: 18591094
• 负责人: KUNISHIMA Shinji
• 金额: $ 2.55万
• 依托单位: Clinical research Center, Nagoya National Hospital.
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591094/
• 关键词: May-Hegglin anomaly; MYH9 disorders; NMMHC-IIA; Congenital thrombocytopenias

MYH9 disorders such as May-Hegglin anomaly are characterized by macrothrombocytopenia and cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, the gene for nonmuscle myosin heavy chain-IIA(NMMHC-IIA). We examined the expression of mutant NMMHC-IIA polypeptide in peripheral blood cells from patients with MYH9 5770delG and 5818delG mutations. A specific antibody to mutant NMMHC-IIA(NT629) was raised against the abnormal carboxyl-terminal residues generated by 5818delG. NT629 reacted to recombinant 5818delG NMMHC-IIA but not to wild-type NMMHC-IIA, and did not recognize any cellular components of normal peripheral blood cells. Immunofluorescence and immunoblotting revealed that mutant NMMHC-IIA was present and sequestrated only in inclusion bodies within neutrophils, diffusely distributed throughout lymphocyte cytoplasm, sparsely localized on a diffuse cytoplasmic background in monocytes, and uniformly distributed at diminished levels only in large platelets. Mutant NMMHC-IIA did not translocate to lamellipodia in surface activated platelets. Wild-type NMMHC-IIA was homogeneously distributed among megakaryocytes derived from the peripheral blood CD34+ cells of patients, but coarse mutant NMMHC-IIA was heterogeneously scattered without abnormal aggregates in the cytoplasm. We show the differential expression of mutant NMMHC-IIA and postulatethat cell-specific regulation mechanisms function in MYH9 disorders.

MYH9疾病，如May-Hegglin异常，以巨血小板减少和细胞质粒细胞包涵体为特征，这是由MYH9突变引起的，MYH9是非肌球蛋白重链iia （NMMHC-IIA）的基因。我们检测了MYH9 5770delG和5818delG突变患者外周血细胞中突变型NMMHC-IIA多肽的表达。针对5818delG产生的异常羧基末端残基，提出了一种针对突变体NMMHC-IIA（NT629）的特异性抗体。NT629对重组5818delG NMMHC-IIA有反应，但对野生型NMMHC-IIA没有反应，并且不识别正常外周血细胞的任何细胞成分。免疫荧光和免疫印迹显示，突变型NMMHC-IIA仅存在于中性粒细胞内的包涵体中并被隔离，弥漫性分布于整个淋巴细胞质中，在单核细胞中稀疏地定位于弥漫性细胞质背景，仅在大血小板中以低水平均匀分布。突变的NMMHC-IIA在表面活化的血小板中没有转移到板足。野生型NMMHC-IIA在患者外周血CD34+细胞衍生的巨核细胞中均匀分布，而粗突变型NMMHC-IIA在细胞质中异质性分散，未见异常聚集。我们展示了突变体NMMHC-IIA的差异表达，并假设细胞特异性调节机制在MYH9疾病中起作用。

项目成果

A boy with MYH9 disorers complilated with congenital heart disease.

一名患有 MYH9 疾病的男孩患有先天性心脏病。

• 发表时间: 2006
• 作者: Ohmori;T;Iwata H. et al.;Kudoh H
• 通讯作者: Kudoh H

Utility of immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-IIA in the differential diagnosis of congenital macrothrombocytopenias.

中性粒细胞非肌肉肌球蛋白重链-IIA 免疫荧光分析在先天性巨血小板减少症鉴别诊断中的应用。

• 发表时间: 2006
• 作者: Mizukami;H;Kuwatsuka Y. et al.;Kunishima S
• 通讯作者: Kunishima S

Differential expression of abnormal myosin in MYH9 disorders.

MYH9 疾病中异常肌球蛋白的差异表达。

• 作者: Suzuki R.;et. al.;Kunishima S
• 通讯作者: Kunishima S

Haematological charactenstics of MYH9 disorders due to MYH9 R702 mutations.

MYH9 R702 突变引起的 MYH9 疾病的血液学特征。

• 发表时间: 2007
• 期刊: Eur H Haematol 78
• 作者: Ono;T;Ito T;Ohmori T;Madoiwa S;Kimura A;小野 智子;Kunishima S;Dagistan N;柏木隆宏;國島伸治;Kimura A;Madoiwa S;Kunishima S
• 通讯作者: Kunishima S

MYH9遺伝子異常を認め、顆粒球と近位尿細管上皮の細胞質にNMMHCA 斑状集積を認めたEpstein 症候群の1例

MYH9基因异常及粒细胞及近端肾小管上皮细胞质NMMHCA斑片状积聚的Epstein综合征一例

• 发表时间: 2007
• 作者: Narimatsu H.;et. al.;今野武津子
• 通讯作者: 今野武津子