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Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes

Abstract

The autosomal dominant, giant-platelet disorders1, May-Hegglin anomaly2,3 (MHA; MIM 155100), Fechtner syndrome4 (FTNS; MIM 153640) and Sebastian syndrome5 (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions (?Döhle-like? bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis4. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 810), which is expressed in platelets9 and upregulated during granulocyte differentiation10. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.

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Figure 1: Electron micrograph of neutrophilic granulocytes in MHA (a) and SBS (b).
Figure 2: ClustalW alignment of the amino acid sequences from class II nonmuscle myosins using the BLASTP program from NCBI (http://www.ncbi.nlm.nih.gov).
Figure 3: A space-filling representation of wild-type chick smooth muscle myosin (b) compared with the mutated residues N93K (a) and R702C (c).

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Acknowledgements

We thank the patients and referring physicians for participation; the ?Fondo Malattie Renali del Bambino? and R. Gusmano for support; and I. Visiers, M. Moxey-Mims and B. Coller for assistance and discussions. This project was supported in part by grants of the Italian Ministry of Health (M. Seri, A.S. & C.L.B.). The Telethon grant E.1313 is gratefully acknowledged (M. Seri). M. Savino is the recipient of a fellowship from the Italian Foundation of Cancer Research (FIRC). R.J.D. was supported in part by grants from the National Institutes of Health, including a Merit Award (5 R37 DK34045), a grant (5 M01 RR00071) for the Mount Sinai General Clinical Research Center and, with J.A.M., a grant (5 P30 HD28822) for the Mount Sinai Child Health Research Center.

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Syndrome Consortium, TH. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nat Genet 26, 103–105 (2000). https://doi.org/10.1038/79063

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