Establishment of Mouse Model of <i>MYH9</i> Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability

<div><p>Nonmuscle myosin heavy chain IIA (NMMHCIIA) encoded by <i>MYH9</i> is associated with autosomal dominantly inherited diseases called <i>MYH9</i> disorders. <i>MYH9</i> disorders are characterized by macrothrombocytopenia and very characteristic inclusion bodies in granulocytes. <i>MYH9</i> 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.</p><p>We generated knock-in mice expressing the <i>Myh9</i> 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.</p><p>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.</p><p>These findings indicate that <i>Myh9</i> R702C knock-in mice mirror features of human <i>MYH9</i> disorders arising from the R702C mutation.</p>