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

The autosomal dominant, giant-platelet disorders(1), May-Hegglin anomaly(2, 3) (MHA; MIM 155100). Fechtner syndrome(4) (FTNS; MIM 153640) and Sebastian syndrome(5) (SBS), share the triad of thrombocytopenia. large platelets an d characteristic leukocyte inclusions ('Dohle-like' bodies). MHA and SBS ca n be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical featu res of sensorineural deafness, cataracts and nephritis(4). 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 c hromosome 22 suggested that all three disorders are allelic. Among the iden tified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10). which is expressed in platelets(9) and upregulated durin g granulocyte differentiation(10). We identified six MYH9 mutations (one no nsense and five missense) in seven unrelated probands from MHA. SBS and FTN S families. On the basis of molecular modelling, the two mutations affectin g the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxytermina l tailpiece. The remaining missense mutations, all affecting highly conserv ed coiled-coil domain positions, imparted destabilizing electrostatic and p olar changes. Thus, our results suggest that mutations in MYH9 result in th ree megakaryocyte/platelet/leukocyte syndromes and are important in the pat hogenesis of sensorineural deafness, cataracts and nephritis.