Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement: hematological, nephrological, and otological studies of heterozygous KO mice.
Among three different isoforms of non-muscle myosin heavy chains (NMMHCs), only NMMHCA is associated with inherited human disease, called MYH9 disorders, characterized by macrothrombocytopenia and characteristic granulocyte inclusions. Here targeted gene disruption was performed to understand fundamental as well as pathological role of the gene for NMMHCA, MYH9. Heterozygous intercrosses yielded no homozygous animals among 552 births, suggesting that MYH9 expression is required for embryonic development. In contrast, MYH9+/- mice were viable and fertile without gross anatomical, hematological, and nephrological abnormalities. Immunofluorescence analysis also showed the normal cytoplasmic distribution of NMMHCA. We further measured the auditory brainstem response and found two of six MYH9+/- mice had hearing losses, whereas the remaining four were comparable to wild-type mice. Such observation may parallel the diverse expression of Alport's manifestations of human individuals with MYH9 disorders and suggest the limited requirement of the gene for maintenance and function of specific organs.
Matsushita
Tadashi
T
Department of Hematology, Nagoya University Graduate School of Medicine, Japan. tmatsu@med.nagoya-u.ac.jp
Hayashi
Hideo
H
Kunishima
Shinji
S
Hayashi
Mutsuharu
M
Ikejiri
Makoto
M
Takeshita
Kyosuke
K
Yuzawa
Yukio
Y
Adachi
Tatsuya
T
Hirashima
Kanji
K
Sone
Michihiko
M
Yamamoto
Koji
K
Takagi
Akira
A
Katsumi
Akira
A
Kawai
Kumi
K
Nezu
Tomoyo
T
Takahashi
Masahide
M
Nakashima
Tsutomu
T
Naoe
Tomoki
T
Kojima
Tetsuhito
T
Saito
Hidehiko
H
D000818:Animals; D001772:Blood Cell Count; D002460:Cell Line; D018390:Gene Targeting / Q000379:methods; D034381:Hearing Loss / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020409:Molecular Motor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009394:Nephritis, Hereditary / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000378:metabolism* / Q000473:pathology*; D014018:Tissue Distribution
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains