title: Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability.
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.
authors: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya City, Aichi Prefecture, Japan.
authors: Nobuaki
authors: N
authors: Suzuki
authors: Shinji
authors: S
authors: Kunishima
authors: Makoto
authors: M
authors: Ikejiri
authors: Shoichi
authors: S
authors: Maruyama
authors: Michihiko
authors: M
authors: Sone
authors: Akira
authors: A
authors: Takagi
authors: Masahito
authors: M
authors: Ikawa
authors: Masaru
authors: M
authors: Okabe
authors: Tetsuhito
authors: T
authors: Kojima
authors: Hidehiko
authors: H
authors: Saito
authors: Tomoki
authors: T
authors: Naoe
authors: Tadashi
authors: T
authors: Matsushita
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D055879:Gene Knock-In Techniques; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D018995:Myosin Heavy Chains; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D013921:Thrombocytopenia / Q000151:congenital* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: C525088:Myh9 protein, mouse; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains
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