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

Abstract

The autosomal dominant, giant-platelet disorders¹, May-Hegglin anomaly^2,3 (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. MYH9; refs 8 10), 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.