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

Macrothrombocytopenia with leukocyte inclusions is a rare autosomal dominan t platelet disorder characterized by a triad of giant platelets, thrombocyt openia, and characteristic Dohle 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 chr omosome 22 allowed a positional candidate approach, and results here indica te that the gene encoding nonmuscle myosin heavy chain-a, NMMHC-A, is mutat ed in this disorder. Mutations were found in 6 of 7 Japanese families studi ed: 3 missense mutations, a nonsense mutation, and a one-base deletion resu lting 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.