Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes
Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes
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DOI：
10.1086/324267
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发表时间：
2001-11-01
影响因子：
9.8
通讯作者：
Martignetti, JA
中科院分区：
文献类型：
--
作者：
Heath, KE;Campos-Barros, A;Martignetti, JA
May-Hegglin异常（MHA）和Fechtner（FTNS）和塞巴斯蒂安（SBS）综合征是常染色体显性血小板疾病，共有巨血小板减少症和特征性白细胞夹杂物。固网服务的其他临床特征包括肾炎、耳聋和白内障。以前，在所有三种疾病中均发现了编码非肌肉肌球蛋白重链IIA（MYHIIA）的非肌肉肌球蛋白重链9基因（MYH 9）突变。现在已经研究了一个大的受影响个体队列（n=27）中的突变谱和基因型-表型和结构-功能关系。此外，已证明MYH 9突变还导致另外两种FTNS样巨血小板减少综合征：Epstein综合征（EPS）和Alport综合征伴巨血小板减少症（APSM）。在所有五种疾病中，在20/27（74%）受影响的个体中鉴定出MYH 9突变。四个突变，R702 C，D1424 N，E1841 K和R1933 X是最常见的。R702 C和R702 H突变仅与FTNS、EPS或APSM相关，因此确定了MYHIIA的一个区域，该区域在巨血小板减少症、肾炎和耳聋的联合发病机制中至关重要。E1841 K、D1424 N和R1933 X卷曲螺旋结构域突变在MHA和FTNS中是常见的。使用三个新的微卫星标记的单倍型分析显示，三个E1841 K载体-一个与MHA和两个与FTNS-共享一个共同的单倍型周围MYH 9基因，这表明一个共同的祖先。两个新的球状头突变K371 N和R702 H，以及最近发现的MYH 9突变R705 H，导致DFNA 17，是基于X射线晶体学数据建模的。总之，我们的数据表明，MHA，SBS，FTNS，EPS和APSM包括一个表型谱的疾病，所有引起的MYH 9突变。根据我们的遗传分析，“MYHIIA综合征”的名称被提议包括所有这些疾病。
May-Hegglin anomaly (MHA) and Fechtner (FTNS) and Sebastian (SBS) syndromes are autosomal dominant platelet disorders that share macrothrombocytopenia and characteristic leukocyte inclusions. FTNS has the additional clinical features of nephritis, deafness, and cataracts. Previously, mutations in the nonmuscle myosin heavy chain 9 gene (MYH9), which encodes nonmuscle myosin heavy chain IIA (MYHIIA), were identified in all three disorders. The spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of affected individuals (n=27) has now been examined. Moreover, it is demonstrated that MYH9 mutations also result in two other FTNS-like macrothrombocytopenia syndromes: Epstein syndrome (EPS) and Alport syndrome with macrothrombocytopenia (APSM). In all five disorders, MYH9 mutations were identified in 20/27 (74%) affected individuals. Four mutations, R702C, D1424N, E1841K, and R1933X, were most frequent. R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. The E1841K, D1424N, and R1933X coiled-coil domain mutations were common to both MHA and FTNS. Haplotype analysis using three novel microsatellite markers revealed that three E1841K carriers-one with MHA and two with FTNS-shared a common haplotype around the MYH9 gene, suggesting a common ancestor. The two new globular-head mutations, K371N and R702H, as well as the recently identified MYH9 mutation, R705H, which results in DFNA17, were modeled on the basis of X-ray crystallographic data. Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations. On the basis of our genetic analyses, the name "MYHIIA syndrome" is proposed to encompass all of these disorders.