Genotype–phenotype correlation in MYH9‐related thrombocytopenia

Abstract

Summary Mutation of the non‐muscle myosin heavy chain type II‐A results in MYH9‐related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May‐Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high‐performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9‐related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C‐terminal coiled coil region or truncation of the tailpiece is associated with haematological‐only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non‐haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype–phenotype relationship.

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

“…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.…”

Phosphorylation of the myosin IIA tailpiece regulates single myosin IIA molecule association with lytic granules to promote NK-cell cytotoxicity

“…18 The patients in this study demonstrated some or all of these symptoms (Table 1), in accordance with previous reports of variable effects of MYH9 mutations. [23][24][25] To determine the effect of these mutations on NK-cell cytotoxicity, eNK cells from these patients were prepared from peripheral blood and immediately evaluated for their ability to kill K562 erythroleukemia cells. Cytotoxicity of the NK-cell preparations was adjusted for purity of the patient and control NK-cell preparations, and the cytotoxic activity of each patient's NK cells was compared with the shipping control for the patient using lytic unit calculations to control for variability in shipping and assay conditions.…”

Historical hematology: May–Hegglin anomaly

“…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.…”