研究者総覧

岩本 禎彦 (イワモト サダヒコ)

  • 人類遺伝学研究部 教授
Last Updated :2021/09/22

研究者情報

学位

  • 医学博士(自治医科大学(JMU))

ホームページURL

J-Global ID

研究キーワード

  • 遺伝疫学   集団遺伝学   多因子遺伝疾患   人類遺伝学   Forensic medicine   Genetic epidemiology   Population Genetics   Polygenic diseases   Human Genetics   

研究分野

  • ライフサイエンス / 医化学
  • ライフサイエンス / システムゲノム科学
  • ライフサイエンス / ゲノム生物学

経歴

  • 2011年04月 - 現在  自治医科大学分子病態治療研究センター・人類遺伝学研究部教授
  • 2004年04月 - 2011年03月  自治医科大学地域医療学センター・人類遺伝学部門教授
  • 2003年04月 - 2004年03月  自治医科大学法医学・人類遺伝学教授
  • 1996年02月 - 2003年03月  自治医科大学法医学・人類遺伝学准教授
  • 1992年04月 - 1996年01月  自治医科大学法医学・人類遺伝学講師
  • 1991年04月 - 1992年03月  自治医科大学法医学・人類遺伝学助教
  • 自治医科大学(JMU)教授

所属学協会

  • 日本免疫学会   電気泳動学会   日本法医学会   日本輸血学会   日本人類遺伝学会   日本臨床血液学会   日本内科学会   

研究活動情報

論文

  • Yuumi Ishizuka, Kazuhiro Nakayama, Ayumi Ogawa, Saho Makishima, Supichaya Boonvisut, Atsushi Hirao, Yusaku Iwasaki, Toshihiko Yada, Yoshiko Yanagisawa, Hiroshi Miyashita, Masafumi Takahashi, Sadahiko Iwamoto
    JOURNAL OF MOLECULAR ENDOCRINOLOGY 52 2 145 - 158 2014年04月 [査読有り][通常論文]
     
    Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P = 9.39 x 10(-7)) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.
  • Kazuhiro Nakayama, Tumenbayer Bayasgalan, Fumiko Tazoe, Yoshiko Yanagisawa, Takaya Gotoh, Kazuhiro Yamanaka, Ayumi Ogawa, Lkhagvasuren Munkhtulga, Ulziiburen Chimedregze, Yasuo Kagawa, Shun Ishibashi, Sadahiko Iwamoto
    HUMAN GENETICS 127 6 685 - 690 2010年06月 [査読有り][通常論文]
     
    Recent genome-wide association studies (GWASs) showed that single nucleotide polymorphisms (SNPs) in FADS1/FADS2 were associated with plasma lipid concentrations in populations with European ancestry. We investigated the associations between the SNPs in FADS1/FADS2 and plasma concentrations of triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in two Asian groups, i.e., Japanese and Mongolians. The genotype of rs174547 (T/C), found to be associated with triglyceride and HDL-C concentrations in the GWAS, was determined in 21,004 Japanese and 1,203 Mongolian individuals. Genotype-phenotype association was assessed by using multiple linear regression models, assuming an additive model of inheritance. The copy number of the rs174547 C allele was significantly associated with increased triglyceride levels (P = 1.5 x 10(-6)) and decreased HDL-C levels (P = 0.03) in the Japanese population. On the other hand, in the Mongolian population, the rs174547 C allele copy number was strongly associated with decreased LDL-C levels (P = 2.6 x 10(-6)), but was not associated with triglyceride and HDL-C levels. The linkage disequilibrium pattern and haplotype structures of SNPs around the FADS1/FADS2 locus showed no marked dissimilarity between Japanese and Mongolian individuals. The present data indicate that the FADS1/FADS2 locus can be added to the growing list of loci involved in polygenic dyslipidemia in Asians. Furthermore, the variable effects of FADS1/FADS2 on plasma lipid profiles in Asians may result from differences in the dietary intake of polyunsaturated fatty acids, which serve as substrates for enzymes encoded by FADS1/FADS2.
  • Lkhagvasuren Munkhtulga, Shuichi Nagashima, Kazuhiro Nakayama, Nanami Utsumi, Yoshiko Yanagisawa, Takaya Gotoh, Toshinori Omi, Maki Kumada, Khadbaatar Zolzaya, Tserenkhuu Lkhagvasuren, Yasuo Kagawa, Hiroyuki Fujiwara, Yoshinori Hosoya, Masanobu Hyodo, Hisanaga Horie, Masayuki Kojima, Shun Ishibashi, Sadahiko Iwamoto
    OBESITY 18 5 1006 - 1014 2010年05月 [査読有り][通常論文]
     
    Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.
  • K. Nakayama, T. Bayasgalan, K. Yamanaka, M. Kumada, T. Gotoh, N. Utsumi, Y. Yanagisawa, M. Okayama, E. Kajii, S. Ishibashi, S. Iwamoto
    JOURNAL OF MEDICAL GENETICS 46 6 370 - 374 2009年06月 [査読有り][通常論文]
     
    Background: Recent genome wide association studies discovered seven novel loci that influence plasma concentrations of triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in Europeans. To date, large scale replication studies using populations with known differences in genome-wide linkage disequilibrium (LD) pattern have not been undertaken. Methods: To address this issue, we tested associations between single nucleotide polymorphisms (SNPs) within the seven novel loci and plasma lipid profiles in 21 010 Japanese individuals. Results: Multiple linear regression analyses showed that the rs3812316 in MLXIPL was strongly associated with triglyceride concentrations (p similar to 3.0x10(-11), 7.1 mg/dl decrease per minor C allele) and that rs599839 in CELSR2/PSRC1/SORT1 was strongly associated with LDL cholesterol concentrations (p similar to 3.1x10(-11), 4.7 mg/dl decrease per minor G allele) in the Japanese population. SNPs near ANGPTL3, TRIB1 and GALNT2 showed evidence for associations with triglyceride concentrations (3.6x10(-6)< p < 5.1x10(-5)). SNP near TRIB1 showed association with LDL cholesterol concentrations (p similar to 1.2x10(-5)). On the other hand, SNPs in NCAN/CILP2/PBX4 and MVK/MMAB were not associated with any plasma lipid profiles in the Japanese population. Ethnic differences in LD pattern would explain the lack of association between these two loci and plasma lipid concentrations in the Japanese population. Conclusion: Associations between the novel loci and plasma lipid concentrations were generally conserved in the Japanese population, with the exception of NCAN/CILP2/PBX4 and MVK/MMAB.
  • Maki Kumada, Munkhtulga Lkhagvasuren, Nanami Utsumi, Toshinori Omi, Takaya Gotoh, Toyomi Kamesaki, Hiroshi Okuda, Eiji Kajii, Sadahiko Iwamoto
    COMMUNITY GENETICS 11 3 150 - 159 2008年 [査読有り][通常論文]
     
    Objective: The aim of the study was to investigate genetic heterogeneity among local Japanese populations. Methods: We performed a single nucleotide polymorphism (SNP) study of four demographically distinct local populations (population 1: a large city; population 2: isolated islands; populations 3 and 4: rural areas). Seventy SNPs in a region spanning 5 Mb of chromosome 17 known to be a candidate region for essential hypertension were genotyped and linkage disequilibrium analyses were performed. Results: Statistical analyses of SNP allele frequencies and haplotype distribution showed significant divergence among the populations, mostly between population 2 and the other populations. Pairwise D' declined with increasing population size, and smaller populations retained a high linkage disequilibrium. Conclusion: Population 2 is likely to have a different ancestry from the majority of the Japanese population, whereas the heterogeneity among the other populations may result from differences in population size or geographic background. Copyright (C) 2008 S. Karger AG, Basel.
  • Lkhagvasuren Munkhtulga, Kazuhiro Nakayama, Nanami Utsumi, Yoshiko Yanagisawa, Takaya Gotoh, Toshinori Omi, Maki Kumada, Batmunkh Erdenebulgan, Khadbaatar Zolzaya, Tserenkhuu Lkhagvasuren, Sadahiko Iwamoto
    HUMAN GENETICS 120 6 879 - 888 2007年01月 [査読有り][通常論文]
     
    Increased levels of retinol binding protein 4 (RBP4) in serum is associated with insulin resistance. To examine this further, the genomic region of RBP4 was genetically surveyed in Mongolian people, who as a group are suffering from a recent rapid increase in diabetes. The RBP4 gene was screened by DHPLC system, and the PCR fragments which showed heteroduplex peaks in multiple samples were followed by direct sequencing to identify common polymorphisms in 48 Mongolian diabetic samples. Identified single nucleotide polymorphisms (SNPs) were genotyped in 511 control and 281 type 2 diabetes samples. The functions of SNPs in the regulatory region were assessed by reporter gene assay and electrophoretic mobility shift assay. Possible association between functional SNPs and serum RBP4 levels or metabolic parameters was statistically assessed. Nine SNPs were identified in the RBP4 gene. A case-control study revealed that the rare alleles of four SNPs were associated with increased risk of diabetes, even after Bonferroni correction (-803, G > A, P = 0.0054; +5169, C > T, P = 0.0025; +6969, G > C, P = 0.0015; +7542, T > del, P = 0.0015). The -803 G > A SNP influenced the transcription efficiency in a hepatocarcinoma cell line as well as the binding efficiency of hepatocyte nuclear factor 1 alpha to the motif. In addition, the -803 A allele was associated with increased serum RBP4 levels in diabetic patients. We have identified a functional SNP in the RBP4 gene associated with type 2 diabetes in Mongolian people.
  • Omi T, Kumada M, Kamesaki T, Okuda H, Munkhtulga L, Yanagisawa Y, Utsumi N, Gotoh T, Hata A, Soma M, Umemura S, Ogihara T, Takahashi N, Tabara Y, Shimada K, Mano H, Kajii E, Miki T, Iwamoto S
    Eur J Hum Genet. 14 1295 - 1305 2006年12月 [査読有り][通常論文]
  • H Suganuma, M Kumada, T Omi, T Gotoh, M Lkhagvasuren, H Okuda, T Kamesaki, E Kajii, S Iwamoto
    FEBS JOURNAL 272 11 2696 - 2704 2005年06月 [査読有り][通常論文]
     
    The rhesus (Rh) blood group antigens are of considerable importance in transfusion medicine as well as in newborn or autoimmune hemolytic diseases due to their high antigenicity. We identified a major DNaseI hypersensitive site at the 5' flanking regions of both RHD and RHCE exon 1. A 34 bp fragment located at -191 to -158 from a translation start position, and containing the TCCCCTCCC sequence, was involved in enhancing promoter activity, which was assessed by luciferase reporter gene assay. A biotin-labelled 34 bp probe isolated an mRNA transporter protein, Aly/REF. The specific binding of Aly/REF to RH promoter in erythroid was confirmed by chromatin immunoprecipitation assay. The silencing of Aly/REF by siRNA reduced not only the RH promoter activity of the reporter gene but also transcription from the native genome. These facts provide second proof of Aly/REF as a transcription coactivator, initially identified as a coactivator for the TCR alpha enhancer function. Aly/REF might be a novel transcription cofactor for erythroid-specific genes.
  • Sadahiko Iwamoto, Toyomi Kamesaki, Maki Kumada, Toshinori Omi, Hiroshi Okuda, Tsuyoshi Hasegawa, Shinji Sakurai, Eiji Kajii
    Legal Medicine 5 4 246 - 250 2003年 [査読有り][通常論文]
     
    We report a clinical mishap based on sample contamination of cytological specimens. Bronchial lavage fluid collected from three male patients was submitted to a pathological institute for cytological diagnosis and to the clinical laboratory in the hospital for tuberculosis screening. Cytological slides of two patients were diagnosed as lung adenocarcinoma and lobectomy was carried out on one patient. However, diagnosis of the surgical specimen was tuberculoma. To resolve the discrepancy, genome DNA was isolated from patients' blood, cytological slide glasses and the mycobacterial culture tubes. Analysis of mitochondrial hyper-variable sequence and microsatellite revealed sample contamination in the cytological slide of the tuberculoma patient. DNA from the mycobacterial culture tubes showed identical results with the cytological slides, suggesting that the contamination occurred at the bed-side. Preservation of part of cytological specimen will be a help to avoid dispute between pathological laboratory and hospital over responsibility of incident. © 2003 Elsevier Ireland Ltd. All rights reserved.
  • S Iwamoto, M Kumada, T Kamesaki, H Okuda, E Kajii, T Inagaki, D Saikawa, K Takeuchi, S Ohkawara, R Takahashi, S Ueda, S Inoue, K Tahara, Y Hakamata, E Kobayashi
    JOURNAL OF BIOLOGICAL CHEMISTRY 277 48 46463 - 46469 2002年11月 [査読有り][通常論文]
     
    We cloned a rat ABO homologue and established human A- and B-transferase transgenic rats. A DNA fragment corresponding to exon 7 of the human ABO gene was amplified from Wistar rat genomic DNA and sequenced. Using the amplified fragments as a probe for Southern blotting, multiple hybridized bands appeared on both EcoRI- and BamHI-digested genomes of seven rat strains, which showed variations in the band numbers among the strains. Four cDNAs were cloned from a Wistar rat, three of which showed A-iransferase activity and one of which showed B-transferase activity. These activities were dependent on the equivalent residues at 266 and 268 of human ABO transferase. Wild Wistar rats expressed A-antigen in salivary gland, intestine, and urinary bladder tissue, but B-antigen was not stained in any organs studied, whereas a transcript from the ABO homologue with B-transferase activity was ubiquitous. Human A-transferase and B-transferase were transferred into Wistar rats. A-transgenic rats expressed A-antigen in ectopic tissue of the brain plexus, type II lung epithelium, pancreas, and epidermis. B-antigen in the B-transgenic rat was expressed in the same organs as A-transgenic rats. These results may shed light on the function and evolution of the ABO gene in primates.
  • Iwamoto S, Kamesaki T, Oyamada T, Okuda H, Kumada M, Omi T, Takahashi J, Tani Y, Omine M, Kajii E
    Am J Hematol. 68 106 - 114 2001年10月 [査読有り][通常論文]
  • S IWAMOTO, E KAJII, T OMI, T KAMESAKI, Y AKIFUJI, S IKEMOTO
    EUROPEAN JOURNAL OF HAEMATOLOGY 50 5 286 - 291 1993年05月 [査読有り][通常論文]
     
    A patient who represented acute hemolytic crisis was studied. Analysis of the erythrocyte membrane proteins by SDS-PAGE revealed a deficiency of band 4.2. In the family, the sister of the patient who had been chemically normal was also shown to be deficient in band 4.2. Binding studies showed that the propositus' membranes were able to bind normal band 4.2 protein as much as control. It was suggested that the binding sites for the protein were prepared on the membrane. We analyzed the band 4.2 cDNA of the propositus and detected a mutation that changes a codon for alanine to one for threonine at residue 142. Band 4.2 exon III of genomic DNA which included the mutation site was amplified and sequenced directly in the family members, and it was revealed that only the homozygotes of the mutation allele manifested band 4.2 deficiency and the parents, who were heterozygotes, showed normal amounts of band 4.2. Recently, the same mutation was reported as Protein 4.2NIPPON in another 4 cases (Bouhassira et al. Blood 1992: 79: 1846-1854). This study supports the hypothesis that this mutation is the pathogenetic cause of band 4.2 deficiency and not a polymorphism.
  • Characterization of a 28-kD polymorphic polypeptide detected by two-dimensional electrophoresis of human platelets.
    S.Iwamoto, E.Kajii, T.Omi, S.Tsuchida, S.Ikemoto
    Hum Hered 42 276 - 279 1992年 [査読有り][通常論文]

書籍

  • 最新血液型学
    ()
    南山堂 1998年

講演・口頭発表等

  • TRIB1は非アルコール性脂肪肝感受性に関わる  [通常講演]
    岩本 禎彦
    62nd Annual Meeting of American Society of Human Genetics 2012年11月 ポスター発表
  • 血清脂質関連Trib1多型は脂肪肝とも関連する  [通常講演]
    岩本禎彦, 石塚裕美, 北村愉介, 巻嶋咲穂, Supichaya Boonvisut, 中山一大, 宮下 洋
    日本人類遺伝学会第57回大会 2012年10月 口頭発表(一般)
  • 内臓脂肪測定ゲノムバンクの構築と候補遺伝子との関連SNP解析  [通常講演]
    岩本禎彦, 石塚裕美, 中山一大, 巻嶋咲穂, 北村愉介, Supichaya Boonvisut, 宮下洋, 柳沢佳子, 片島充弘, 恩田智彦, 福島省吾, 岡田浩一
    第33回日本肥満学会 2012年10月 ポスター発表
  • Mixed genomeを用いた血清脂質関連遺伝子のリシークエンス  [通常講演]
    岩本禎彦, 石塚裕美, 小川歩美, 中山一大
    日本人類遺伝学回第56回大会 2011年11月 口頭発表(一般)
  • 新規血清脂質レベル関連遺伝子Trib1導入マウス肝臓のトランスクリプトーム解析  [通常講演]
    岩本禎彦, 石塚裕美, 小川歩美, 中山一大
    第32回日本肥満学会 2011年09月 口頭発表(一般)
  • 糖感受性エレメントのTRIB1遺伝子脂質異常症関連領域へのマッピングと遺伝子機能解析  [通常講演]
    岩本禎彦, 石塚裕美, 小川歩美, 後藤孝也, 中山一大
    第17回日本遺伝子診療学会 2010年08月 口頭発表(一般)

作品等

  • 先端医科学の地域医療への展開
    2003年 -2008年
  • ミレニアム・プロジェクト疾患遺伝子研究・高血圧研究グループ
    2001年 -2004年
  • Characterization of 28KD polymorphic polypeptide detected by two-dimensional electrophoresis of human platelets.
    1991年

MISC

  • 日本人の血清脂質を規定する遺伝子座
    岩本 禎彦 Annual Review糖尿病・代謝・内分泌 2012 118 -125 2012年 [査読無し][通常論文]
  • S Iwamoto, H Suganuma, T Kamesaki, T Omi, H Okuda, E Kajii JOURNAL OF BIOLOGICAL CHEMISTRY 275 (35) 27324 -27331 2000年09月 [査読有り][通常論文]
     
    fRhesus-associated glycoprotein is a critical co-factor in the expression of rhesus blood group antigens. We identified and cloned an erythroid-specific major DNase I-hypersensitive site located about 10 kilobases upstream from the translation start site of the RHAG gene. A short core enhancer sequence of 195 base pairs that corresponded with the major hypersensitive site and possessed position- and orientation-independent enhancer activity in K562 cells. In vitro DNase I footprint analysis revealed four protected regions in the core enhancer; two GATA motifs, an Ets-like motif and an unknown motif. The GATA motifs bound GATA-1 and mutagenesis analysis revealed that the proximal one is critical for the enhancing activity. Homology plot analysis using the 5' sequence of the mouse RHAG gene revealed four homologous stretches and multiple insertions of repetitive sequences among them; four LINE/L1 and four Alu in the human and as well as one LINE/L1 and one LTR/MaLR in the mouse gene. The highly conservative enhancer region was flanked by SINE and LINE/L1 in both species. These results suggest that the 5'-flanking sequence of RHAG gene is a preferable target sequence for retroviral transposition and that the enhancer was inserted in the same manner, resulting in the acquisition of erythroid dominant expression.
  • S Iwamoto, M Yamasaki, M Kawano, H Okuda, T Omi, J Takahashi, Y Tani, M Omine, E Kajii INTERNATIONAL JOURNAL OF HEMATOLOGY 68 (3) 257 -268 1998年10月 [査読有り][通常論文]
     
    Rh blood group antigens are associated with non-glycosylated human erythrocyte membrane proteins encoded by two closely related genes, RHCE and RHD, and with a glycoprotein, a critical co-er;pressing factor encoded by the RH50 gene. The sequence analysis of RHCE transcripts has revealed that RhE/e and C/c serological phenotypes are associated with a nucleotide substitution in exon 5 and six substitutions in exons 1 and 2 of RHCE gene, respectively. Smythe et al, have shown that the full length transcript of RhcE gene expressed c and E antigens and the transcript of RhD gene expressed D and G antigens, using retroviral-mediated gene transduction into K562 cells. We performed an epitope analysis of Rh antigen by constructing retroviral gene coding six RH cDNAs, which contain RhcE, ce, CE and D cDNAs, and CE-D, D-CE chimera cDNAs. The cDNAs were introduced into KU812E cells and the expressed antigens were analyzed by flow cytometry. These studies revealed that the C/c and E/e associated substitutions actually participated in respective polymorphic epitopes. However, the C antigen was not detected on the KU812E cells introduced with CE cDNA, despite E antigen being expressed. The study with the chimera gene between CE and D cDNAs also indicated that the Rh epitopes were not constructed with short polymorphic exofacial peptide loops only but also with other peptide fragments and membrane components. Go-expression studies of Rh50 and RhD or cE gene in non-erythroid cells, 293, and expression studies of Rh50 in another erythroid cell, HEL, did not show any Rh antigens on the transduced cells, despite the Northern blot study showing both transcripts in the cells. It was suggested that at least a second co-expressing factor was needed to express RhCE or D antigens on the plasma membrane. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.
  • S Iwamoto, T Omi, M Yamasaki, H Okuda, M Kawano, E Kajii BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 243 (1) 233 -240 1998年02月 [査読有り][通常論文]
     
    The Rh blood group antigens are carried by two distinct but homologous membrane proteins encoded by two closely related genes, RHCE and RHD. Rh50 glycoprotein is the membrane protein tightly associated with Rh polypeptides and is critical for expression of Rh antigens. The amino acid sequence and predicted membrane topology of Rh50 glycoprotein are significantly homologous with those of the Rh proteins. Northern blot analysis of leukemic cell lines showed that expression of RH50 gene is restricted to cells with erythroid features. HEL and K562 cells showed a transcription levels ratio of 1 to 9.9 for Rh50, and 12.3 to 1 for Rh. The nucleotide sequence of 5' flanking region of RH50 gene and functional promoter assays also supported the erythroid-specific regulation of the gene, whereas the sequence had lower homology with the promoter sequence of RH genes. Seven GATAs, nine E-boxes, two CACCCs, one YY1, and one October motif were identified in the 1868bp 5' flanking sequence. The core promoter of RH50 gene was located within 68bp length from the translation start position, which included an inverse GATA motif, although obvious motifs for Sp1 or erythroid Kruppel-like factor were lacking. The inverse GATA motif was the target sequence of GATA-1 protein, and disruption of the motif abolished the transactivating activity of erythroid cells. These studies confirm the erythroid-specific expression of Rh antigens, but suggest distinct regulatory mechanisms for RH vs RH50 genes. (C) 1998 Academic Press.
  • S Iwamoto, JP Li, N Sugimoto, H Okuda, E Kajii BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 222 (3) 852 -859 1996年05月 [査読有り][通常論文]
     
    We have previously identified a novel first exon of Duffy gene and two inverse GATA motifs in the 600 bp 5' flanking region. The proximal GATA is positioned downstream from the start position of endothelium and upstream from that of erythroid. One base substitution (-365T-->C) was found in the proximal GATA motif from three black Fy(a-b-) individuals, and was regarded as a common polymorphic mutation in black Fy(a-b-) individuals. The upstream sequence of the novel first exon was inserted in the upstream of chloramphenicol acetyltransferase (CAT) gene and transfected in human erythroleukemia cell line (HEL) and human microvascular endothelial cells (HMvEC). The black type mutation abolished the CAT transcription in HEL cells but not in HMvEC. Deletion mutagenesis study revealed that the proximal GATA motif represent the erythroid regulatory core region for Duffy gene. Gel shift assay showed that the proximal GATA motif is the target sequence of GATA-1. These studies indicate that the black type mutation abolishes Duffy gene expression in erythroid but not in postcapillary venule endothelium, which is compatible with the Northern blot and immunohistochemical observation in black Fy(a-b-) individuals. (C) 1996 Academic Press, Inc.
  • S Iwamoto, JP Li, T Omi, S Ikemoto, E Kajii BLOOD 87 (1) 378 -385 1996年01月 [査読有り][通常論文]
     
    The Duffy gene has been shown not to be split by introns, even in its 5' untranslated region, and to be expressed not only in erythroid but in postcapillary venule endothelium of almost every organ in the body, To further investigate the transcriptional start position in erythroid and postcapillary venule endothelium. we performed 5'-rapid amplification of cDNA ends (5'-RACE). While every positive clone of 5'-RACE encoded the identical sequence of previously identified cDNA downstream from nucleotide 203, the upstream sequences were different The upstream sequences corresponded to the sequence from nucleotide -279 to -308/-357 in erythroblasts and from -279 to -355/-383 in lung and were regarded as comprising a novel axon. This novel exon encoded seven residues initiated with a methionine, linked to nucleotide 203 in-frame and in agreement with the GT-AG splicing rule. The major erythroid transcriptional start position was identified in human erythroleukemia cells by primer extension and in bone marrow by ribonuclease protection analysis at 34 bases upstream from the first ATG codon, Distinctively, in lung and kidney, the transcription was started at 82 bases upstream from the ATG. Both Northern blotting and reverse transcription-polymerase chain reaction followed by Southern analysis indicated a predominance of the novel spliced form of mRNA of about 50- to 200-fold comparing with the unspliced form, in every studied organ and erythroid lineage cells. The spliced form of cDNA has been transfected into a human erythroleukemic cell line, K562, and the expressed protein reacted with Duffy-specific murine monoclonal antibody Fy6. These studies indicate that the product from the spliced form of mRNA is the major product of the Duffy gene in the erythroid lineage and postcapillary venule endothelium. (C) 1996 by The American Society of Hematology.
  • S IWAMOTO, T OMI, E KAJII, S IKEMOTO BLOOD 85 (3) 622 -626 1995年02月 [査読有り][通常論文]
     
    The Duffy blood group antigen has been characterized by its roles on red blood cells: as a receptor for the malarial parasites and as a promiscuous receptor for chemokine superfamily. Recently, the Duffy blood group associated glycoprotein D (gpFy) cDNA has been cloned (Chaudhuri et al: Proc Natl Acad Sci USA 90:10793, 1993). In this report we describe the organization of genomic DNA coding for the gpFy and elucidate the molecular nature of Fy(a/b) polymorphisms. By a Southern blotting analysis probed with gpFy cDNA. gpFy gene was shown to be composed of three DNA fragments; 1.1-kb Sac I, 1.9-kb EcoRI, and their intervening 47-bp fragments. We cloned the 1.1-kb Sac I and 1.9-kb EcoRI fragments by inverted polymerase chain reaction (IPCR) procedure. The promoter region of the gpFy gene was cloned by IPCR of 1.1-kb Sac I fragment and the 3' flanking sequence was cloned by IPCR of 1.9 kb EcoRI fragment. The both IPCR products contained on both side the known gpFy cDNA sequence without introns, as expected. Although no TATA or CCAAT boxes are present in the promoter sequence, several transcription factor binding site motifs are contained, including AP-1, HNF-5, TCF-1, ApoE B2, W-element, H-APF-1, and Sp-l. The 3' flanking region has two additional polyadenylation signals, other than that used in the cDNA, and also has an indirect and a direct repeat sequence clustered with the 5' flanking region. These facts indicate a possibility that the gpFy gene has been evolved by multiple retrotransposition events. By comparing the coding area of the gpFy gene in 28 Duffy-positive individuals, we elucidated that one base change that results in an amino acid substitution [GA-T(Asp(44)) -->t GGT(Gly)] is in accordance with the Fy(a)/Fy(b) polymorphism. This fact proves that the gpFy cDNA and its gene described in this report encode the Duffy blood group system. (C) 1995 by The American Society of Hematology.
  • S IWAMOTO, E NISHIUMI, E KAJII, S IKEMOTO BLOOD 83 (4) 1017 -1023 1994年02月 [査読有り][通常論文]
  • 腹水を合併した慢性リンパ性白血病
    内科 55 1985年 [査読無し][通常論文]

受賞

  • 1996年 日本輸血学会学術奨励賞
     JPN

共同研究・競争的資金等の研究課題

  • 生活習慣病の遺伝学
    共同研究
    研究期間 : 2003年 -2008年
  • Genetics of polygenic diseases
    Cooperative Research
    研究期間 : 2003年 -2008年
  • Genetics polygenic diseases
    Cooperative Research
    研究期間 : 2003年 -2008年
  • 血液型の分子遺伝学
    受託研究
    研究期間 : 1992年
  • Molecular genetics of blood group antigens
    Funded Research
    研究期間 : 1992年
  • 遺伝子多型と生活習慣病
  • Genetic polymorphism and life style oriented diseases


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