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, 69 (5), 1033-45

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


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

K E Heath et al. Am J Hum Genet.


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.


Figure  1
Figure 1
Schematic representation of MYH9 genomic structure (not drawn to scale) and the spectrum of mutations identified in the MYH9 gene. The 40 coding exons and the promoter (noncoding exon A) are represented by vertical colored bars. Intron A (Int A) contains enhancer elements. Mutations shown above the genomic structure have been identified in this cohort or in our previous study (May-Hegglin/Fechtner Syndrome Consortium , indicated by a superscript “1”). Mutations shown below the genomic structure have been reported by other groups (Kelly et al. [“2”]; Kunishima et al. [“3”]; Lalwani et al. [“4”]). Clinical disorders are color-coded as shown in the key. Red mutations indicate the purely hematological disorders. Within this group, individuals with MHA are labeled in red, those with SBS are in red and underlined, and those in whom a diagnosis of MHA or SBS could not been differentiated are marked with an asterisk (*).
Figure  2
Figure 2
A, Chromosome location of MYH9 and of the microsatellite markers used in the haplotype analysis. Drawing is not to scale. Physical distances are indicated. Heterozygosity (Htz) values for each marker are shown, as determined from the Marshfield Medical Research Foundation human genetic map or by the amplification of DNA from 95 healthy white control individuals (data not shown). B, Haplotype analysis of markers flanking the MYH9 locus in three E1841K carriers. Shared haplotype is indicated in boldface, and genotypes where phase was determined are underlined. M = E1841K mutation. Individual A was reported in our previous study as “individual 3” (May-Hegglin/Fechtner Syndrome Consortium 2000).
Figure  3
Figure 3
Clustal W alignment of the human MYHIIA amino acid sequence with the amino acid sequences of nonmuscle and smooth-muscle myosins, using the BLASTP program from NCBI. The predicted affected amino acids for the identified missense mutations are shown in boxes. Conserved amino acid changes at the positions of the mutated residues are underlined. Abbreviations and GenBank accession numbers are as follows: Hs MYHIIA, Homo sapiens MYHIIA (accession number P35579); Rn MYHA, Rattus norvegicus nonmuscle myosin heavy chain A (accession number AAA74950); Rn neur MHC, R. norvegicus neuronal myosin heavy chain (accession number S21801); Gg MYHIIA, Gallus gallus MYHIIA (accession number AAA48974); Xl MYHIIA, Xenopus laevis MYHIIA (accession number AAC83556); Hs MYHIIB, H. sapiens MYHIIB (accession number AAA99177); Rn MYHB, R. norvegicus nonmuscle myosin heavy chain B (accession number AAF61445); Bt MYHB, Bos taurus MYHB (accession number BAA36494); Gg MYHIIB, G. gallus MYHIIB (accession number AAA48988); Xl MYHB, X. laevis MYHIIB (accession number AAA49915); Gg SMMHC, G. gallus SMMHC (accession number P10587); Oc SM2, Oryctolagus cuniculus smooth-muscle myosin 2 (accession number P35748); Mm SM2, Mus musculus SM2 (accession number JC5421); Dm NMII, Drosophila melanogaster nonmuscle myosin heavy chain II (accession number AAB09049); and Ce NMYII, Caenorhabditis elegans nonmuscle myosin heavy chain II (accession number AAA83339).
Figure  4
Figure 4
A space-filling representation of the wild-type chick smooth-muscle myosin (b) compared with the mutated residues R702H (a) and R705H (c); This 4.5-Å radial sphere was derived from the X-ray crystallographic structure (Dominguez et al. 1998), as described in the Subjects and Methods section. d, Possible interactions of wild type. e, Ablation of these interactions in the R705H mutation. f, Alpha helical conformation of wild type. g, Potential stabilization of mutation K371N.

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