Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome)

Abstract

Macrothrombocytopenia with leukocyte inclusions is a rare autosomal dominant platelet disorder characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like leukocyte inclusions. A previous study mapped a locus for the disease on chromosome 22q12.3-q13.2 by genome-wide linkage analysis. In addition, the complete DNA sequence of human chromosome 22 allowed a positional candidate approach, and results here indicate that the gene encoding nonmuscle myosin heavy chain-A, NMMHC-A, is mutated in this disorder. Mutations were found in 6 of 7 Japanese families studied: 3 missense mutations, a nonsense mutation, and a one-base deletion resulting in a premature termination. Immunofluorescence studies revealed that NMMHC-A distribution in neutrophils appeared to mimic the inclusion bodies. These results provide evidence for the involvement of abnormal NMMHC-A in the formation of leukocyte inclusions and also in platelet morphogenesis.

Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders

“…1,2 We previously showed diffuse NMMHC-IIA distribution in lymphocytes from patients with MYH9 disorders. 5,11 We found that both wild-type and mutant NMMHC-IIA were diffusely distributed in the lymphocyte cytoplasm ( Figure 3B). Although the original report of MayHegglin anomaly described that inclusion bodies are absent in monocytes, this remains controversial.…”

“…NMMHC-IIA is homogeneously distributed in the cytoplasm of normal resting platelets. 5,11,20,21 PRB440P diffusely stained the cytoplasm of platelets from the patients, and intensely stained the cell periphery ( Figure 3A,B left panels). In contrast, most platelets were negative for NT629 staining ( Figure 3A,B right panels) and only those that were similar to or larger than erythrocytes (ϳ 10% of total platelets) were weakly stained in the cytoplasm but not in the cell periphery ( Figure 3D).…”

“…[1][2][3] These disorders are caused by heterozygous mutations in MYH9, which encodes nonmuscle myosin heavy chain-IIA (NMMHC-IIA), and include the May-Hegglin anomaly, Sebastian, Fechtner, and Epstein syndromes, Alport-like syndrome with macrothrombocytopenia, and nonsyndromic deafness (DFNA17). [4][5][6] An MYH9 mutation is always associated with macrothrombocytopenia and granulocyte inclusion bodies from birth, but it does not predict the development of Alport manifestations, including nephritis, deafness, and cataracts. A mutation of MYH9 alone does not seem to cause associated Alport manifestations, and unknown genetic and/or epigenetic factors might influence the phenotypic consequences of MYH9 mutations.…”

Historical hematology: May–Hegglin anomaly

“…The pathogenesis of this disorder was totally unknown until recently, when the disease locus was mapped to chromosome 22q12.3-q13.2 by linkage analysis [10,11]. The gene responsible for the disorder was then identified by a positional candidate gene approach as MYH9, which encodes a large cytoplasmic protein (NMMHC-IIA) [12][13][14]. NMMHC-IIA is expressed in many different tissues, including platelets, leukocytes, kidney, and cochlea and is involved in cell motility, cytokinesis, cell polarity, and cell architecture.…”

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

“…However, a surveillance strategy with regular blood counts may identify patients in an earlier stage of the leukemia, thus reducing the risk for bleeding and infectious complications and increase cure rates. Therefore, we suggest a stepwise diagnostic algorithm in which the most frequent causes of hereditary thrombocytopenia (e.g., MayHegglin anomaly and Fechtner syndrome [13][14][15][16]) are excluded by clinical investigations and subsequently AML1 mutational analyses are performed. Fig.…”