Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Curr Opin Hematol. 2010 Sep;17(5):405-10. doi: 10.1097/MOH.0b013e32833c069c.
MYH9 disorders are autosomal dominant macrothrombocytopenias with leukocyte inclusion bodies caused by mutations in MYH9, the gene for the nonmuscle myosin heavy chain IIA. May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes belong to MYH9 disorders. The present review summarizes the recent advances in genetic diagnosis and our understanding of the pathogenetic mechanisms of MYH9 mutations and the development of nonhematological complications.
A genotype-phenotype cohort study showed that patients with an MYH9 mutation in the motor head domain of myosin IIA have severe macrothrombocytopenia and are at a high risk for the development of glomerulonephritis and deafness. Among these, Arg702 mutations are associated with the most severe phenotype. In-vitro studies on cultured megakaryocytes elucidated that myosin IIA inhibits proplatelet formation. The loss of myosin IIA function owing to MYH9 mutations promotes proplatelet formation and may trigger precocious and premature platelet release, resulting in macrothrombocytopenia. Giant platelets only residually express mutant myosin IIA that has a loss of function and cannot participate in the reorganization of cytoskeletal contractile structures. Renal histopathological and immunochemical studies have suggested that glomerulonephritis in MYH9 disorders is caused by podocyte malfunction owing to defects in the myosin IIA structure and MYH9 expression.
MYH9 disorders are not merely benign hematological abnormalities, but serious syndromic disorders affecting the kidney, inner ear, and lens. A genetic diagnosis is mandatory for an accurate prognosis of nonhematological complications and management or possibly prophylactic treatment.
常染色体显性遗传的巨大血小板综合征（MYH9 病）的特征为血小板体积增大，白细胞内包涵体，由 MYH9 基因突变引起，编码非肌性肌球蛋白重链ⅡA。其中包括 May-Hegglin 异常、Sebastian 综合征、Fechtner 综合征和 Epstein 综合征。本文就 MYH9 基因突变的遗传诊断以及对其发病机制和非血液学并发症的理解方面的最新进展作一综述。
一项基因型-表型队列研究显示，肌球蛋白ⅡA 马达头部结构域突变的患者具有严重的巨血小板减少症，且发生肾小球肾炎和耳聋的风险较高。其中 Arg702 突变与最严重的表型相关。体外培养巨核细胞研究表明，肌球蛋白ⅡA 抑制前血小板形成。由于 MYH9 基因突变导致肌球蛋白ⅡA 功能丧失，促进了前血小板的形成，并可能引发过早和过早的血小板释放，导致巨血小板减少症。巨大血小板仅残留表达具有功能丧失的突变肌球蛋白ⅡA，无法参与细胞骨架收缩结构的重组。肾脏组织病理学和免疫化学研究提示 MYH9 病中的肾小球肾炎是由于肌球蛋白ⅡA 结构和 MYH9 表达缺陷导致的足细胞功能障碍所致。
MYH9 病不仅是良性的血液学异常，还是累及肾脏、内耳和晶状体的严重综合征。遗传诊断对于非血液学并发症的准确预后、管理或可能的预防性治疗至关重要。
