Abstract
Nonmuscle myosin heavy chain IIA (NMMHCIIA) encoded by MYH9 is associated with autosomal dominantly inherited diseases called MYH9 disorders. MYH9 disorders are characterized by macrothrombocytopenia and very characteristic inclusion bodies in granulocytes. MYH9 disorders frequently cause nephritis, sensorineural hearing disability and cataracts. One of the most common and deleterious mutations causing these disorders is the R702C missense mutation.We generated knock-in mice expressing the Myh9 R702C mutation. R702C knock-in hetero mice (R702C+/− mice) showed macrothrombocytopenia. We studied megakaryopoiesis of cultured fetal liver cells of R702C+/− mice and found that proplatelet formation was impaired: the number of proplatelet tips was decreased, proplatelet size was increased, and proplatelet shafts were short and enlarged. Although granulocyte inclusion bodies were not visible by May–Grünwald Giemsa staining, immunofluorescence analysis indicated that NMMHCIIA proteins aggregated and accumulated in the granulocyte cytoplasm.In other organs, R702C+/− mice displayed albuminuria which increased with age. Renal pathology examination revealed glomerulosclerosis. Sensory hearing loss was indicated by lowered auditory brainstem response.These findings indicate that Myh9 R702C knock-in mice mirror features of human MYH9 disorders arising from the R702C mutation.
Highlights
May-Hegglin Anomaly (MHA) is an autosomal-dominant inherited disorder characterized by macrothrombocytopenia and Dohle body-like cytoplasmic inclusion bodies in granulocytes
Generation of R702C+/2 mice In order to investigate the molecular and pathological mechanisms underlying human MYH9 disorders, we introduced a Myh9 R702C mutation into the mouse genome using a knock-in approach (Figure 1)
D1424N and E1841K mice were generated using the conventional knock-in technique that we employed, but their R702C hetero mice were generated by disrupting the Myh9 exon 2 and replacing it with human NMMHCIIA fused to eGFP (GFP-R702C mice)
Summary
May-Hegglin Anomaly (MHA) is an autosomal-dominant inherited disorder characterized by macrothrombocytopenia and Dohle body-like cytoplasmic inclusion bodies in granulocytes. We and others showed that MYH9, which encodes nonmuscle myosin heavy chain IIA (NMMHCIIA), is mutated in this disorder [1,2,3]. MYH9 is expressed in hematological cells, as well as in kidney, cochlea and lens cells. Patients with a MYH9 mutation often suffer from nephritis, deafness and cataracts. A new disease entity, MYH9 disorders, has been proposed to encompass a wide variety of clinical phenotypes [4,5]. More than 40 MYH9 mutations have been reported. The R702C mutation is associated with the development of nephritis and hearing loss in young patients [6,7,8]
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