title: Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A.
abstract: We have generated 3 mouse lines, each with a different mutation in the nonmuscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9-related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease.
authors: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1583, USA.
authors: Yingfan
authors: Y
authors: Zhang
authors: Mary Anne
authors: MA
authors: Conti
authors: Daniela
authors: D
authors: Malide
authors: Fan
authors: F
authors: Dong
authors: Aibing
authors: A
authors: Wang
authors: Yelena A
authors: YA
authors: Shmist
authors: Chengyu
authors: C
authors: Liu
authors: Patricia
authors: P
authors: Zerfas
authors: Mathew P
authors: MP
authors: Daniels
authors: Chi-Chao
authors: CC
authors: Chan
authors: Elliot
authors: E
authors: Kozin
authors: Bechara
authors: B
authors: Kachar
authors: Michael J
authors: MJ
authors: Kelley
authors: Jeffrey B
authors: JB
authors: Kopp
authors: Robert S
authors: RS
authors: Adelstein
mesh_terms: D000818:Animals; D002386:Cataract / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005804:Genes, Lethal; D034381:Hearing Loss / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains; D024507:Nonmuscle Myosin Type IIA / Q000502:physiology*; D010976:Platelet Count; D013921:Thrombocytopenia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
chemical_list: C525088:Myh9 protein, mouse; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains