A case of MYH9 disorders caused by a novel mutation (p.K74E).

Abstract

Dear Editor, MYH9 disorders are rare hereditary autosomal dominant disorders characterized by macrothrombocytopenia and Dohle body-like cytoplasmic inclusion bodies in granulocytes [1–3]. Though most MYH9 disorders are caused by missense mutations, differences in the location or the type of amino acid substitution can result in differences in phenotypes of blood cells or Alport manifestations (nephritis, sensory deafness, and cataract) [4]. Mutations in the head domain of nonmuscle myosin heavy chain-IIA (NMMHC-IIA) cause MYH9 disorders with a high frequency of Alport manifestations [4, 5]. It is sometimes difficult to identify cytoplasmic inclusion bodies in granulocytes by May-Giemsa staining, which often leads to a misdiagnosis of the condition as immune thrombocytopenic purpura (ITP). Here, we report a 40-year-old woman with MYH9 disorders who had been diagnosed with ITP in her childhood. When she was 35 years old, she developed renal failure, and hemodialysis was initiated 3 years later. Symptoms are inherited in an autosomal dominant manner (Fig. 1a). Results of laboratory testing were as follows: WBC 9.3×10/L, RBC 4.65×10/L, Hb 136 g/L, Plt 55× 10/L. On her peripheral blood smear, there were giant platelets and Dohle body-like cytoplasmic inclusion bodies in granulocytes (Fig. 1b). Immunofluorescence staining for NMMHC-IIA revealed abnormal NMMHC-IIA localization (Fig. 1c). Pure-tone audiogram showed bilateral sensorineural hearing loss. Genetic analysis showed p.K74E mutation in exon 1. The NMMHC-IIA sequence alignments near K74 are highly conserved residues among species. Based on the crystal structure of highly homologous smooth muscle myosin, K74 is located near the SH1-helix in the head domain (Fig. 1d). The detection of abnormal NMMHC-IIA localization by immunofluorescence staining is gold standard for diagnosis of MYH9 disorders [6]. Indeed, in the present case, cytoplasmic inclusion bodies in granulocytes were seen more clearly with immunofluorescence analysis than with May-Giemsa staining. The pattern of cytoplasmic inclusion bodies is strongly associated with the type of mutation, and the localization pattern of NMMHC-IIA can be classified into several groups based on the number, size, and shape of the aggregated NMMHC-IIA granules [6]. In patients with rod domain mutation, NMMHC-IIA forms one or two large intensely stained cytoplasmic foci. In patients with head domain mutation, the inclusion bodies are sometimes invisible with May-Giemsa staining, whereas immunofluorescence shows small cytoplasmic spots with circular to oval shapes. Because SH1-helix in the head domain of NMMHC-IIA is a critical segment for ATP hydrolysis and interaction with actin [4, 7, 8], patients with mutation in SH1-helix (e.g., p.R702C, p.R702H, * Nobuaki Suzuki suzukin@med.nagoya-u.ac.jp