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

Suzuki, Nobuaki; Kunishima, Shinji; Ikejiri, Makoto; Maruyama, Shoichi; Sone, Michihiko; Takagi, Akira; Ikawa, Masahito; Okabe, Masaru; Kojima, Tetsuhito; Saito, Hidehiko; Naoe, Tomoki; Matsushita, Tadashi

doi:https://doi.org/10.1371/journal.pone.0071187

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

Suzuki, Nobuaki; Kunishima, Shinji; Ikejiri, Makoto et al.

PLoS ONE, 2013, 8(8), e71187

Number of Access:1,550（2025-12-17 23:05 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/78605

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Title	Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability
Creator	NRID 1000070637686 1000070637686 CreatorName Suzuki, Nobuaki
	NRID 1000060373495 1000060373495 CreatorName Kunishima, Shinji
	CreatorName Ikejiri, Makoto
	NRID 1000010362253 1000010362253 CreatorName Maruyama, Shoichi
	NRID 1000030273238 1000030273238 CreatorName Sone, Michihiko
	NRID 1000030135371 1000030135371 CreatorName Takagi, Akira
	NRID 1000020304066 1000020304066 ORCID 0000-0001-9859-6217 0000-0001-9859-6217 researchmap permalink read0054910 read0054910 Scopus Author ID 16689054500 16689054500 CreatorName Ikawa, Masahito
	NRID 1000030089875 1000030089875 CreatorName Okabe, Masaru
	NRID 1000040161913 1000040161913 CreatorName Kojima, Tetsuhito
	NRID 1000020153819 1000020153819 CreatorName Saito, Hidehiko
	NRID 1000050217634 1000050217634 CreatorName Naoe, Tomoki
	NRID 1000030314008 1000030314008 CreatorName Matsushita, Tadashi
Description	Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability. Suzuki N, Kunishima S, Ikejiri M, Maruyama S, Sone M, et al. 2013. 8(8) doi:10.1371/journal.pone.0071187
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.
Publisher	Public Library of Science
Source Title	PLoS ONE
Volume (Issue)	8(8)
Page	e71187
Date of Issued	2013-08-20
Language	English
Handle URL	https://hdl.handle.net/11094/78605
eISSN	19326203
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1371/journal.pone.0071187
Relation.isIdenticalTo	PMID 23976996
Access Rights	open access
CopyRight	© 2013 Suzuki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	PLoS ONE. 2013, 8(8), p. e71187
DC.title	Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability
DC.creator	Suzuki, Nobuaki
	Kunishima, Shinji
	Ikejiri, Makoto
	Maruyama, Shoichi
	Sone, Michihiko
	Takagi, Akira
	Ikawa, Masahito
	Okabe, Masaru
	Kojima, Tetsuhito
	Saito, Hidehiko
	Naoe, Tomoki
	Matsushita, Tadashi
DC.publisher	Public Library of Science
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2013-08-20
DC.identifier	https://doi.org/10.1371/journal.pone.0071187
DC.description	Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability. Suzuki N, Kunishima S, Ikejiri M, Maruyama S, Sone M, et al. 2013. 8(8) doi:10.1371/journal.pone.0071187
DCTERMS.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.
DC.rights	© 2013 Suzuki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DC.format	78605
citation_title	Establishment of Mouse Model of MYH9 Disorders: Heterozygous R702C Mutation Provokes Macrothrombocytopenia with Leukocyte Inclusion Bodies, Renal Glomerulosclerosis and Hearing Disability
citation_author	Suzuki, Nobuaki
	Kunishima, Shinji
	Ikejiri, Makoto
	Maruyama, Shoichi
	Sone, Michihiko
	Takagi, Akira
	Ikawa, Masahito
	Okabe, Masaru
	Kojima, Tetsuhito
	Saito, Hidehiko
	Naoe, Tomoki
	Matsushita, Tadashi
citation_publisher	Public Library of Science
citation_language	English
citation_date	2013-08-20
citation_journal_title	PLoS ONE
citation_volume	8
citation_issue	8
citation_firstpage	e71187
citation_doi	https://doi.org/10.1371/journal.pone.0071187
citation_pmid	23976996
citation_public_url	https://hdl.handle.net/11094/78605

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

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