Identification of six novel MYH9 mutations and genotype–phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions

Abstract

The autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS), and Fechtner syndrome (FTNS), are rare platelet disorders characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like leukocyte inclusions. The locus for these disorders was previously mapped on chromosome 22q12.3-q13.2 and the disease gene was recently identified as MYH9, the gene encoding the nonmuscle myosin heavy chain-A. To elucidate the spectrum of MYH9 mutations responsible for the disorders and to investigate genotypephenotype correlation, we examined MYH9 mutations in an additional 11 families and 3 sporadic patients with the disorders from Japan, Korea, and China. All 14 patients had heterozygous MYH9 mutations, including three known mutations and six novel mutations (three missense and three deletion mutations). Two cases had Alport manifestations including deafness, nephritis, and cataracts and had R1165C and E1841K mutations, respectively. However, taken together with three previous reports, including ours, the data do not show clear phenotype-genotype relationships. Thus, MHA, SBS, and FTNS appear to represent a class of allelic disorders with variable phenotypic diversity.

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

“…9 All of the patients had moderate-to-severe thrombocytopenia, but none had a bleeding tendency. Patient 2 and the father of patient 1 who also had an MYH9 mutation had been diagnosed with idiopathic thrombocytopenic purpura and treated accordingly.…”

“…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. [7][8][9][10] Although the molecular mechanisms of hematologic abnormalities are under investigation, those of the kidney, cochlea, and lens are completely unknown.…”

“…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. [7][8][9][10] Although the molecular mechanisms of hematologic abnormalities are under investigation, those of the kidney, cochlea, and lens are completely unknown.We previously showed that NMMHC-IIA polypeptide accumulates in neutrophil cytoplasm and forms inclusion bodies in patients with MYH9 disorders. The nature of the cytoplasmic accumulation can be classified according to the number, size, and shape of accumulated NMMHC-IIA granules, into types I, II, and III.…”

Historical hematology: May–Hegglin anomaly

“…Although they were previously considered to be separate clinical entities, it is now established that all four disorders are caused by mutations in the MYH9 gene. Therefore, the name ''MYH9 disorder'' or ''MYH9-related disease'' has been proposed [15,[19][20][21]. To date, about 200 families with MYH9 disorders have been studied, in which 30 distinct mutations in the MYH9 gene have been identified [19][20][21][22].…”

“…Therefore, the name ''MYH9 disorder'' or ''MYH9-related disease'' has been proposed [15,[19][20][21]. To date, about 200 families with MYH9 disorders have been studied, in which 30 distinct mutations in the MYH9 gene have been identified [19][20][21][22]. The majority of patients are heterozygous for missense mutations and some patients are heterozygous for nonsense or frameshift mutation in the last exon.…”