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Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A.
- Source :
-
Blood [Blood] 2012 Jan 05; Vol. 119 (1), pp. 238-50. Date of Electronic Publication: 2011 Sep 08. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Cataract metabolism
Cataract pathology
Female
Fluorescent Antibody Technique
Genes, Lethal
Hearing Loss metabolism
Hearing Loss pathology
Heterozygote
Homozygote
Humans
Immunoblotting
Kidney Diseases metabolism
Kidney Diseases pathology
Male
Megakaryocytes metabolism
Mice
Mice, Transgenic
Myosin Heavy Chains
Platelet Count
Thrombocytopenia metabolism
Thrombocytopenia pathology
Cataract etiology
Disease Models, Animal
Hearing Loss etiology
Kidney Diseases etiology
Megakaryocytes pathology
Mutation genetics
Nonmuscle Myosin Type IIA physiology
Thrombocytopenia etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 119
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 21908426
- Full Text :
- https://doi.org/10.1182/blood-2011-06-358853