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Syndecan-4 deficiency leads to high mortality of lipopolysaccharide- injected mice 査読有り

"Ishiguro, K., Kadomatsu, K., Kojima, T., Muramatsu, H., Iwase, M., Yoshikai, Y., Yanada, M., Yamamoto, K., Matsushita, T., Nishimura, M., Kusugami, K., Saito, H. and Muramatsu, T."

J Biol Chem 3 巻頁： 3 2001年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared to wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1b was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1b was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor (TGF)-b1 was impaired in the syndecan-4- deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of TGF-b1 on IL-1b production."

Plasma levels of syndecan-4 (ryudocan) are elevated in patients with acute myocardial infarction 査読有り

"Kojima, T., Takagi, A., Maeda, M., Segawa, T., Shimizu, A., Yamamoto, K., Matsushita, T. and Saito, H."

Thromb Haemost 85 巻 ( 5 ) 頁： 793-9 2001年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Syndecan-4 (ryudocan) is a cell-surface heparan sulfate proteoglycan, which plays an important role in a variety of biological functions including regulation of blood coagulation. cell adhesion, and cell growth. In this study, we measured plasma levels of syndecan-4 in patients with acute myocardial infarction using an enzyme-immunoassay, and found that they were extremely high, with a peak of average (10.5 +/- 5.6 ng/ml, 2 weeks after onset), as compared with those in normal subjects (0.078 +/- 0.030 ng/ml) (p < 0.001). We also observed a distinct expression of syndecan-4 in the repair region of the damaged cardiac tissues with infarction, but not in intact region, by immunohistochemical analysis. To clarify the mechanism of syndecan-4 induction, we investigated the hypoxia effect on its expression, and found that hypoxia treatment up-regulated the gene expression of syndecan-4 in various types of cells. Taken together, it is suggested that syndecan-4 is induced by hypoxia stimuli in ischemic heart tissues, and may function as a tissue-repair molecule via biological mediators such as heparin-binding growth factors."

Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions 査読有り

"Kunishima, S., Matsushita, T., Kojima, T., Amemiya, N., Choi, Y. M., Hosaka, N., Inoue, M., Jung, Y., Mamiya, S., Matsumoto, K., Miyajima, Y., Zhang, G., Ruan, C., Saito, K., Song, K. S., Yoon, H. J., Kamiya, T. and Saito, H."

J Hum Genet 46 巻 ( 12 ) 頁： 722-9 2001年

記述言語：英語掲載種別：研究論文（学術雑誌）

"The autosomal dominant macrothrombocytopenia with leukocyte inclusions, May-Hegglin anomaly (MHA), Sebastian syndrome (SBS), and Fechtner syndrome (FTNS), are rare platelet disorders characterized by a triad of giant platelets, thrombocytopenia, and characteristic Dohle body-like leukocyte inclusions. The locus for these disorders was previously mapped on chromosome 22q12.3-q13.2 and the disease gene was recently identified as MYH9, the gene encoding the nonmuscle myosin heavy chain-A. To elucidate the spectrum of MYH9 mutations responsible for the disorders and to investigate genotypephenotype correlation, we examined MYH9 mutations in an additional 11 families and 3 sporadic patients with the disorders from Japan. Korea, and China. All 14 patients had heterozygous MYH9 mutations, including three known mutations and six novel mutations (three missense and three deletion mutations). Two cases had Alport manifestations including deafness, nephritis, and cataracts and had R1165C and E1841K mutations, respectively. However, taken together with three previous reports, including ours, the data do not show clear phenotype-genotype relationships. Thus, MHA, SBS, and FTNS appear to represent a class of allelic disorders with variable phenotypic diversity."

"Binding site on human von Willebrand factor of bitiscetin, a snake venom-derived platelet aggregation inducer" 査読有り

"Matsui, T., Hamako, J., Matsushita, T., Nakayama, T., Fujimura, Y. and Titani, K."

Biochemistry 41 巻 ( 25 ) 頁： 7939-46. 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Bitiscetin, a C-type lectin-like heterodimeric snake venom protein purified from Bitis arietans, binds to human von Willebrand factor (VWF) and induces the platelet membrane glycoprotein (GP) Ib-dependent platelet agglutination in vitro similar to botrocetin. In contrast with botrocetin which binds to the A1 domain of VWF, the A3 domain, a major collagen-binding site of VWF, was proposed to be a bitiscetin-binding site. In the competitive binding assay, neither bitiscetin nor botrocetin had an inhibitory effect on the VWF binding to the immobilized type III collagen on a plastic plate. The anti-VWF monoclonal antibody NMC-4, which inhibits VWF-induced platelet aggregation by binding to alpha4 helix of the A1 domain, also inhibited bitiscetin binding to the VWF. Binding of VWF to the immobilized bitiscetin was competitively inhibited by a high concentration of botrocetin. A panel of recombinant VWF, in which alanine-scanning mutagenesis was introduced to the charged amino acid residues in the A1 domain, showed that the bitiscetin-binding activity was reduced in mutations at Arg632, Lys660, Glu666, and Lys673 of the A1 domain. Those substituted at Arg629, Arg636, and Lys667, which decreased the botrocetin binding, showed no effect on the bitiscetin binding. These results indicate that bitiscetin binds to a distinct site in the A1 domain of VWF spanning over alpha4a, alpha5 helices and the loop between alpha5 and beta6 but close to the botrocetin- and NMC-4-binding sites. Monoclonal antibodies recognizing the alpha-subunit of bitiscetin specifically inhibited bitiscetin-induced platelet agglutination without affecting the binding between VWF and bitiscetin, suggesting that the alpha-subunit of bitiscetin is located on VWF closer to the GPIb-binding site than the beta-subunit is. Bitiscetin and botrocetin might modulate VWF by binding to the homologous region of the A1 domain to induce a conformational change leading to an increased accessibility to platelet GPIb."

Identification of the regulatory elements of the human von Willebrand factor for binding to platelet GPIb. Importance of structural integrity of the regions flanked by the CYS1272-CYS1458 disulfide bond 査読有り

"Nakayama, T., Matsushita, T., Dong, Z., Sadler, J. E., Jorieux, S., Mazurier, C., Meyer, D., Kojima, T. and Saito, H."

J Biol Chem 277 巻 ( 24 ) 頁： 22063-72. 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

"In vitro platelet glycoprotein Ib (GPIb) binding of the human von Willebrand factor (VWF) increases markedly by exogenous modulators such as ristocetin or botrocetin, and the binding does not occur in normal circulation. GPIb binding sites have been assigned in the VWF A1 domain, which consists of a disulfide loop Cys1272(509)-Cys1458(695) where amino acid residues are numbered from the starting methionine as +1. The previous numbering from the N-terminal Ser of the mature processed VWF is indicated in parentheses. In contrast, several gain-of- function mutations have been found in two regions comprised of the disulfide loop and its N- and C-terminal flanking regions. In this study, Cys1222(459)-Tyr1271(508), Gln1238(475)-Tyr1271(508), Glu1260(497)-Tyr1271(508), and Asp1459(696)-Asp1472(709) were sequentially deleted of full-length multimeric recombinant VWF. Deletions at either side resulted in normal GPIb binding, indicating that the flanking regions are not GPIb binding sites. However, the addition of a mutation at Arg1308(545) on each deletion mutant resulted in spontaneous GPIb binding without requiring modulators, suggesting that both regions are important for the inhibition of GPIb binding. Spontaneous binding was completely inhibited by monoclonal antibodies that recognize the GPIb binding sites. Interestingly, mutant proteins with N-terminal but not C-terminal deletions lost binding to monoclonal antibodies B328, B710, and 23C7, which selectively inhibit ristocetin- induced GPI binding. Their epitopes were found at His1268(505) or Asp1269(506). The crystallographic structure of the A1 domain suggests that GPIb binding is influenced by the molecular interface between the two regions and that the antibody binding to the interface inhibits binding."

Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin- deficient mice 査読有り

"Yanada, M., Kojima, T., Ishiguro, K., Nakayama, Y., Yamamoto, K., Matsushita, T., Kadomatsu, K., Nishimura, M., Muramatsu, T. and Saito, H."

Blood 99 巻 ( 7 ) 頁： 2455-8. 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Antithrombin (AT) deficiency is an autosomal disorder associated with venous thromboembolism. However, a diagnosis of homozygous AT deficiency is seldom made. Most patients are heterozygous and have approximately 50% AT activities, and they are at higher risk for the development of thromboembolism. Through gene targeting we generated AT- deficient mice and previously reported that completely AT-deficient mice could not survive the prenatal period because of extensive thrombosis in the myocardium and liver sinusoids. In contrast, heterozygous AT-deficient mice with 50% AT activities have not shown spontaneous thromboembolic episodes. To demonstrate a thrombotic tendency in heterozygous AT deficiency, we challenged heterozygous AT- deficient mice (AT+/- mice) with the administration of lipopolysaccharide (LPS) or with restraint stress by immobilization. LPS injection markedly induced fibrin deposition in the kidney glomeruli, myocardium, and liver sinusoids in AT+/- mice compared with wild-type mice (AT+/+ mice). Restraint stress tests were performed by placing mice in 50-mL conical centrifuge tubes for 20 hours. Fibrin deposition was observed in the kidney of AT+/+ and AT+/- mice, but AT+/- mice exhibited more extensive fibrin deposition than AT+/+ mice. After prophylactic administration of human AT concentrates to increase plasma AT activities of AT+/- mice, LPS-induced fibrin deposition was effectively prevented. These results suggest that heterozygous AT deficiency is significantly associated with a tendency toward thrombosis formation in the kidney. The AT+/- mouse thus is a useful model for studying the effect of environmental or genetic risk factors on thrombogenesis."

Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, ""Klotho"" mouse 査読有り

"Takeshita, K., Yamamoto, K., Ito, M., Kondo, T., Matsushita, T., Hirai, M., Kojima, T., Nishimura, M., Nabeshima, Y., Loskutoff, D. J., Saito, H. and Murohara, T.

Semin Thromb Hemost 28 巻 ( 6 ) 頁： 545-54 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

Although aging accompanies specific pathological changes, including thrombosis and organ sclerosis, the underlying mechanisms of these processes remain to be elucidated. In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant (kl/kl) mice. Active PAI-1 antigen in plasma and PAI-1 mRNA in several tissues were strikingly elevated in kl/kl mice as compared with wild-type mice. This increased PAI-1 expression was age dependent and linked to the development of ectopic calcification and glomerular fibrin deposition in the kidneys. In situ hybridization analysis of kl/kl mice demonstrated that strong signals for PAI-1 mRNA were localized in renal tubular epithelial cells, cardiomyocytes, adrenal medullar cells, and smooth muscle and endothelial cells in Monckeberg's arteriosclerotic vessels. Renal glomerular fibrin deposition, as evaluated immunohistochemically, was occasionally observed only in kl/kl mice, and the number of fibrin-positive glomeruli increased as the kl/kl mice aged. These observations suggest that in the process of aging the PAI-1 gene expression is increased, contributing to the development of thrombosis.

Novel nonsense mutation in the platelet glycoprotein Ibbeta gene associated with Bernard-Soulier syndrome 査読有り

"Kunishima, S., Matsushita, T., Ito, T., Kamiya, T. and Saito, H."

Am J Hematol 71 巻 ( 4 ) 頁： 279-84 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder caused by quantitative or qualitative abnormalities in the glycoprotein (GP) Ib/IX/V complex, the platelet receptor for von Willebrand factor. This complex is composed of four subunits, GPIbalpha, GPIbbeta, GPIX, and GPV, and the coordinated assembly of GPIbalpha, GPIbbeta, and GPIX is required for the efficient surface expression of a functional complex. We report here a novel nonsense mutation of the GPIbbeta gene associated with BSS. Flow cytometric analysis of the patient's platelets showed markedly reduced GPIbalpha and absent GPIX surface expression. Immunoblot analysis of solubilized platelets showed that a small amount of GPIbalpha was detected; however, GPIbbeta and GPIX were undetectable. DNA sequencing analysis revealed a novel nonsense mutation of the GPIbbeta gene that converts Trp (TGG) to a stop codon (TAG) at residue 123. Transient transfection studies revealed that the mutant GPIbbeta polypeptide was not detected in the transfected 293T cells, suggesting that null expression of the mutant GPIbbeta impairs expression of the GPIbalpha and GPIX subunits and results in a BSS phenotype in the patient."

Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations 査読有り

"Kunishima, S., Matsushita, T., Kojima, T., Sako, M., Kimura, F., Jo, E. K., Inoue, C., Kamiya, T. and Saito, H."

Lab Invest 83 巻 ( 1 ) 頁： 115-22 2003年

記述言語：英語掲載種別：研究論文（学術雑誌）

"In this study, a total of 24 cases with MYH9 disorders and suspected cases were subjected to immunofluorescence analysis by a polyclonal antibody against human platelet NMMHCA. Abnormal subcellular localization of NMMHCA was observed in every neutrophil from individuals with MYH9 mutations. Comparison with May-Grunwald-Giemsa staining revealed that the NMMHCA always coexisted with the neutrophil inclusion bodies, suggesting that NMMHCA is associated with such bodies. In three cases, neutrophil inclusions were not detected on conventional May-Grunwald-Giemsa-stained blood smears but immunofluorescence analysis revealed the abnormal NMMHCA localization. In contrast, cases with Epstein syndrome and the isolated macrothrombocytopenia with normal NMMHCA localization had no MYH9 mutations. An antibody that recognizes the C-terminal 12 mer peptides showed similar immunoreactivity from the patients heterozygous for truncated mutations that abolished the C-terminal epitope, suggesting that normal NMMHCA dimerizes with abnormal NMMHCA to form inclusion bodies. We further propose that the localization pattern can be classified into three groups according to the number, size, and shape of the fluorescence-labeled NMMHCA granule. Immunofluorescence analysis of neutrophil NMMHCA is useful as a screening test for the clear hematopathologic classification of MYH9 disorders."

Compound heterozygosity for two novel mutations in a severe factor XI deficiency 査読有り

"Tsukahara, A., Yamada, T., Takagi, A., Murate, T., Matsushita, T., Saito, H. and Kojima, T."

Am J Hematol 73 巻 ( 4 ) 頁： 279-84 2003年

記述言語：英語掲載種別：研究論文（学術雑誌）

"We identified two novel mutations in an asymptomatic 25-year-old Japanese patient with severe factor XI deficiency. Direct sequencing analysis of PCR products from his factor XI gene revealed a G to T transversion in exon 12, resulting in the nonsense mutation (Glu447Stop) and a G insertion in five consecutive guanine nucleotides ((501)Trp(TGG)-(502)Gly(GGG)) in exon 13 that is expected to lead to the substitution of the last 105 amino acids ((503)Tyr-(607)Val) with 32 abnormal amino acid residues ((503)Val-(534)Thr) followed by stop codon. We also demonstrated that two mutations are associated with the separate alleles in this patient, indicating compound heterozygosity for these mutations. Both mutations lead to the disruption of the catalytic domain structure of the FXI molecule and thus are responsible for his deficiency of factor XI."

"Enzyme immunoassay for measurement of murine plasminogen activator inhibitor-1, employing a specific antibody produced by the DNA vaccine method" 査読有り

"Yamada, T., Takagi, A., Takeshita, K., Yamamoto, K., Ito, M., Matsushita, T., Murate, T., Saito, H. and Kojima, T."

Thromb Res 111 巻頁： 285-91 2003年

記述言語：英語掲載種別：研究論文（学術雑誌）

"We developed a sensitive immunoassay to determine the concentration of mouse plasminogen activator inhibitor-1. The assay was a non-competitive sandwich enzyme-linked immunosorbent assay (ELISA) based on the production of a specific polyclonal antibody against mouse plasminogen activator inhibitor type-1 (PAI-1) used both as a trapping and detecting antibody. This antibody was raised in a rabbit by direct introduction of the expression vector plasmid DNA encoding mouse PAI-1, instead of conventional immunization with the purified protein. The standard curve was constructed with a recombinant glutathione S-transferase (GST)-mouse PAI-1 fusion protein (GST-mPAI-1) and dose-response of the assay was linear for GST-mPAI-1 between 6.25 and 100 pM. In order to assess the consistency of the assay, we measured PAI-1 antigen in normal mouse pooled plasma several times. We found that the intra-assay and inter-assay coefficients of variation (CV) were 4.8% and 9.2%, respectively, indicating that the ELISA would be sufficiently repeatable and reproducible. In this assay, lipopolysaccharide (LPS)-injected mice showed substantially higher levels (22-fold) of plasma PAI-1 antigen than did control mice (12.5+/-2.4 vs. 0.58+/-0.16 nM), similar to results reported elsewhere. Taken together, the DNA vaccine method is extremely useful for preparing specific antibodies against mouse PAI-1, which can be utilized to establish the ELISA and analyze the profile of PAI-1 distributions in mice under various conditions. This approach might also be useful for immunological investigation of other coagulation factors and related proteins."

*Identification of the Amino Acid Residues of the Platelet Glycoprotein Ib (GPIb) Essential for the von Willebrand Factor Binding by Clustered Charged-to-Alanine Scanning Mutagenesis 査読有り

"Shimizu, A., Matsushita, T., Kondo, T., Inden, Y., Kojima, T., Saito, H. and Hirai, M."

J Biol Chem 279 巻 ( 16 ) 頁： 16285-94 2004年

記述言語：英語掲載種別：研究論文（学術雑誌）

At the site of vascular injury, von Willebrand factor (VWF) mediates platelet adhesion to subendothelial connective tissue through binding to the N-terminal domain of the alpha chain of platelet glycoprotein Ib (GPIbalpha). To elucidate the molecular mechanisms of the binding, we have employed charged-to-alanine scanning mutagenesis of the soluble fragment containing the N-terminal 287 amino acids of GPIbalpha. Sixty-two charged amino acids were changed singly or in small clusters, and 38 mutant constructs were expressed in the supernatant of 293T cells. Each mutant was assayed for binding to several monoclonal antibodies for human GPIbalpha and for ristocetin-induced and botrocetin-induced binding of (125)I-labeled human VWF. Mutations at Glu(128), Glu(172), and Asp(175) specifically decreased both ristocetin- and botrocetin-induced VWF binding, suggesting that these sites are important for VWF binding of platelet GPIb. Monoclonal antibody 6D1 inhibited ristocetin- and botrocetin-induced VWF binding, and a mutation at Glu(125) specifically reduced the binding to 6D1. In contrast, antibody HPL7 had no effect for VWF binding, and mutant E121A reduced the HPL7 binding. Mutations at His(12) and Glu(14) decreased the ristocetin-induced VWF binding with normal botrocetin-induced binding. Crystallographic modeling of the VWF-GPIbalpha complex indicated that Glu(128) and Asp(175) form VWF binding sites; the binding of 6D1 to Glu(125) interrupts the VWF binding of Glu(128), but HPL7 binding to Glu(121) has no effect on VWF binding. Moreover, His(12) and Glu(14) contact with Glu(613) and Arg(571) of VWF A1 domain, whose mutations had shown similar phenotype. These findings indicated the novel binding sites required for VWF binding of human GPIbalpha.

Identification of protein Salpha gene mutations including four novel mutations in eight unrelated patients with protein S deficiency 査読有り

"Okada, H., Takagi, A., Murate, T., Adachi, T., Yamamoto, K., Matsushita, T., Takamatsu, J., Sugita, K., Sugimoto, M., Yoshioka, A., Yamazaki, T., Saito, H. and Kojima, T."

Br J Haematol 126 巻 ( 2 ) 頁： 219-25 2004年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Eight distinct and potentially causative mutations were identified in eight unrelated Japanese patients with protein S (PS) deficiency, by direct DNA sequencing of the protein Salpha (PSalpha) gene-specific polymerase chain reaction products of all 15 exons and exon/intron boundaries. There were five missense mutations, including two novel mutations (Cys80Tyr and Arg314His), and three showed a major impact on the expected gene products: novel mutations of a 5-bp deletion (delCTCTG887:Cys206Stop) and a nonsense mutation (Glu208Stop), as well as a previously reported splice site (exon 10 +5 A-->G) mutation. One of the patients showed compound heterozygosity for delCTCTG887 and 732A-->G. Investigation for the cosegregation state of these two mutations with PS deficiency in the patient's family suggested that the delCTCTG887 mutation was responsible for the abnormal phenotype and that the 732A-->G (Lys155Glu) mutation did not appear to play a key role. However, we also identified the same 732A-->G (Lys155Glu) mutation in an unrelated patient with apparent PS deficiency with severe pulmonary embolism, and found that this mutation seemed to cosegregate with a PS-deficient state in her family members. These data implied that unknown factor(s) other than the 732A-->G mutation itself might influence phenotypic expression of PS status in different individuals."

*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 査読有り

Matsushita, T., Hayashi, H., Kunishima, S., Hayashi, M., Ikejiri, M., Takeshita, K., Yuzawa, Y., Adachi, T., Hirashima, K., Sone, M., Yamamoto, K., Takagi, A., Katsumi, A., Kawai, K., Nezu, T., Takahashi, M., Nakashima, T., Naoe, T., Kojima, T. and Saito, H.

Biochem Biophys Res Commun 325 巻 ( 4 ) 頁： 1163-71 2004年

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

First description of somatic mosaicism in MYH9 disorders 査読有り

"Kunishima, S., Matsushita, T., Yoshihara, T., Nakase, Y., Yokoi, K., Hamaguchi, M. and Saito, H."

Br J Haematol 128 巻 ( 3 ) 頁： 360-5 2005年

記述言語：英語掲載種別：研究論文（学術雑誌）

"MYH9 disorders are characterized by giant platelets, thrombocytopenia, and Dohle body-like cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, which encodes non-muscle myosin heavy chain-A (NMMHCA). These disorders are known to be transmitted in an autosomal dominant manner, although about 20% of cases are considered to be sporadic. We report here the first case of a MYH9 disorder because of somatic mosaicism. The patient was the father of a male with typical May-Hegglin anomaly. The father had normal platelet counts, however, both normal-sized and giant platelets were observed on his peripheral blood smears. In addition, 14% of neutrophils contained inclusion bodies and the rest showed a normal morphology. Quantitative fluorescent polymerase chain reaction analysis showed that only 6% of DNA from peripheral blood leucocytes harboured the mutation. The mosaicism was demonstrated at a similar rate in different tissues, buccal mucosa cells and hair bulb cells, implying that the mutation had occurred before gastrulation. Mosaicism might account for some de novo mutations in MYH9 disorders."

Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness 査読有り

"Kunishima, S., Matsushita, T., Shiratsuchi, M., Ikuta, T., Nishimura, J., Hamaguchi, M., Naoe, T. and Saito, H."

Eur J Haematol 74 巻 ( 1 ) 頁： 1-5 2005年

記述言語：英語掲載種別：研究論文（学術雑誌）

"MYH9 disorders are autosomal-dominant macrothrombocytopenias with leukocyte inclusions caused by mutations in the MYH9 gene, which encodes the non-muscle myosin heavy chain-A (NMMHCA). We report a patient with an MYH9 disorder who presented with macrothrombocytopenia without leukocyte inclusions and severe bilateral sensory deafness. Conventional May-Grunwald-Giemsa staining failed to detect granulocyte cytoplasmic inclusions, whereas immunofluorescence analysis clearly demonstrated abnormal neutrophil NMMHCA localization. Genetic analyses revealed a novel heterozygous 18 base deletion in MYH9, leading to a six-amino acid in-frame deletion (N76_S81del) in NMMHCA. These results further support the usefulness of immunofluorescence analysis in differential diagnosis of MYH9 disorders."

Obesity enhances the induction of plasminogen activator inhibitor-1 by restraint stress: a possible mechanism of stress-induced renal fibrin deposition in obese mice 査読有り

"Yamamoto, K., Kojima, T., Adachi, T., Hayashi, M., Matsushita, T., Takamatsu, J., Loskutoff, D. J. and Saito, H."

Journal of Thrombosis and Haemostasis 3 巻 ( 7 ) 頁： 1495-1502 2005年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Summary. Background and objectives: Cardiovascular/thrombotic diseases are frequently induced by a variety of stressors. Obese patients are susceptible to thrombotic diseases associated with stress, but the underlying mechanism is still unknown. We have begun to investigate the expression of a primary inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), in association with tissue thrombosis, using restraint-stressed obese mice. Methods and results: We analyzed the expression of PAI-1 after restraint (immobilization) stress in genetically obese mice in comparison with their lean counterparts. Dramatic increases in PAI-1 antigen in plasma and in tissue extracts were observed in the obese mice exposed to restraint stress. The induction of PAI-1 mRNA by stress in the tissues was also pronounced in the stressed obese mice as compared with the lean mice, especially in the hearts and adipose tissues. In situ hybridization analysis revealed that strong signals for PAI-1 mRNA were localized in the adipocytes, cardiovascular endothelial cells, and renal glomerular cells of the stressed obese mice. Histological examination revealed that renal glomerular fibrin deposition was detected only in the obese mice after 2 h of restraint stress. Conclusions: Obesity enhances the stress-mediated PAI-1 induction in the blood and tissues. This phenomenon may be associated with the increased risk of stress-induced renal fibrin deposition in obese subjects."

Integrin activation and matrix binding mediate cellular responses to mechanical stretch 査読有り

"Katsumi, A., Naoe, T., Matsushita, T., Kaibuchi, K. and Schwartz, M. A."

J Biol Chem 280 巻 ( 17 ) 頁： 16546-9 2005年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Mechanical tension is a critical determinant of cell growth, differentiation, apoptosis, migration, and development. Integrins have been implicated in sensing force but little is known about how forces are transduced to biochemical signals. We now show that mechanical strain stimulates conformational activation of integrin alphavbeta3 in NIH3T3 cells. Integrin activation is mediated by phosphoinositol 3-kinase and is followed by an increase in integrin binding to extracellular matrix proteins. Mechanical stretch stimulation of JNK was dependent on new integrin binding to extracellular matrix. These data define a molecular mechanism for the role of integrins in mechanotransduction."

Giant platelet syndrome 査読有り

"Saito, H., Matsushita, T., Yamamoto, K., Kojima, T. and Kunishima, S."

Hematology 10 Suppl 1 巻頁： 41-6 2005年

Identification of amino acid residues essential for heparin binding by the A1 domain of human von Willebrand factor 査読有り

"Adachi, T., Matsushita, T., Dong, Z., Katsumi, A., Nakayama, T., Kojima, T., Saito, H., Sadler, J. E. and Naoe, T."

Biochem Biophys Res Commun 339 巻 ( 4 ) 頁： 1178-83 2006年

記述言語：英語掲載種別：研究論文（学術雑誌）

"Platelet adhesion is mediated by von Willebrand factor (VWF) that binds platelet glycoprotein Ib (GPIb). Previous observations suggested that heparin competitively inhibits the binding of VWF to GPIb and may down-regulate platelet adhesion. We performed charged-to-alanine scanning mutagenesis of domain A1 and studied dose-dependent binding to heparin-Sepharose beads. Mutations at Lys1362 and Arg1395, at which the GPIb binding was markedly decreased, showed 41% and 42% binding, respectively. Clustered mutations in the segments 1332KDRKR1336 and 1405KKKK1408, which have been proposed as heparin binding sequences, showed 72% and 52% binding, respectively. However, single alanine substitutions within these clusters showed normal binding. Our findings suggest that heparin may inhibit the binding of VWF to GPIb by interacting with GPIb binding and interpret why some hemorrhagic complications of heparin therapy are not predictable based on techniques for monitoring the conventional anticoagulant effects of heparin."

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