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Establishment of mouse model of MYH9 disorders: heterozygous R702C mutation provokes macrothrombocytopenia with leukocyte inclusion bodies, renal glomerulosclerosis and hearing disability.
- Source :
-
PloS one [PLoS One] 2013 Aug 20; Vol. 8 (8), pp. e71187. Date of Electronic Publication: 2013 Aug 20 (Print Publication: 2013). - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Blood Platelets metabolism
Blood Platelets pathology
Brain Stem metabolism
Brain Stem physiopathology
Cell Differentiation
Disease Models, Animal
Female
Fetus
Gene Knock-In Techniques
Granulocytes metabolism
Granulocytes pathology
Hearing Loss, Sensorineural genetics
Hearing Loss, Sensorineural physiopathology
Hepatocytes metabolism
Hepatocytes pathology
Heterozygote
Humans
Inclusion Bodies pathology
Kidney metabolism
Kidney physiopathology
Male
Mice
Myosin Heavy Chains
Nonmuscle Myosin Type IIA metabolism
Primary Cell Culture
Thrombocytopenia genetics
Thrombocytopenia pathology
Thrombocytopenia physiopathology
Brain Stem pathology
Hearing Loss, Sensorineural pathology
Kidney pathology
Mutation, Missense
Nonmuscle Myosin Type IIA genetics
Thrombocytopenia congenital
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23976996
- Full Text :
- https://doi.org/10.1371/journal.pone.0071187