Nonmuscle Myosin Heavy Chain IIA Mutations Define a Spectrum of Autosomal Dominant Macrothrombocytopenias: May-Hegglin Anomaly and Fechtner, Sebastian, Epstein, and Alport-Like Syndromes

Abstract

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.

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

“…We did this by mutating Arg709 to Cys, thereby duplicating a mutation that had previously been shown to occur in humans for NMHC II-A (Heath et al, 2001). Interestingly, the homologous residue has also been shown to be mutated in NMHC II-C, although, in this case, to a serine residue (Donaudy et al, 2004).…”

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.…”

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.…”