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| 1.
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Chinen, Yasutsugu ; Yanagi, Kumiko ; Nakamura, Sadao ; Nakayama, Noriko ; Kamiya, Motoko ; Nakayashiro, Mami ; Kaname, Tadashi ; Naritomi, Kenji ; Nakanishi, Koichi
概要:
Carnitine-acylcarnitine translocase (CACT) deficiency is a fatty acid ß-oxidation disorder of the carnitine shuttle in m
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itochondria, with a high mortality rate in childhood. We evaluated three patients, including two siblings, with neonatal-onset CACT deficiency and revealed identical homozygous missense mutations of p.Arg275Gln within the SLC25A20 gene. One patient died from hypoglycemia and arrhythmia at 26 months; his pathological autopsy revealed increased and enlarged mitochondria in the heart but not in the liver.
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| 2.
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Yonamine, Tomoko ; Kaname, Tadashi ; Chinen, Yasutsugu ; Tamashiro, Kouichi ; Kosuge, Noritake ; Saito, Seiichi
概要:
Hereditary leiomyomatosis and renal cell cancer is a rare, inherited disease caused by mutations in the fumarate hydrata
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se gene. It is characterized by cutaneous leiomyomas, uterine leiomyomas, and/or renal cell cancer. We present the case of a 42-year-old woman with a heterozygous missense mutation (p.M195T) in the fumarate hydratase gene. Although the patient did not have cutaneous leiomyoma and she had no family history of hereditary leiomyomatosis and renal cell cancer, the presence of early onset symptomatic uterine leiomyoma and type 2 papillary renal cell cancer confirmed the diagnosis of hereditary leiomyomatosis and renal cell cancer.
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| 3.
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Chinen, Yasutsugu ; Nakamura, Sadao ; Kaneshi, Takuya ; Nakayashiro, Mami ; Yanagi, Kumiko ; Kaname, Tadashi ; Naritomi, Kenji ; Nakanishi, Koichi
概要:
Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A-associ
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ated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.
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| 4.
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Chinen, Yasutsugu ; Nakamura, Sadao ; Ganaha, Akira ; Hayashi, Shin ; Inazawa, Johji ; Yanagi, Kumiko ; Nakanishi, Koichi ; Kaname, Tadashi ; Naritomi, Kenji
概要:
A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge,
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mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.
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| 5.
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Kozuka, Chisayo ; Kaname, Tadashi ; Shimizu-Okabe, Chigusa ; Takayama, Chitoshi ; Tsutsui, Masato ; Matsushita, Masayuki ; Abe, Keiko ; Masuzaki, Hiroaki
概要:
Aims/hypothesis Overeating of dietary fats causes obesity in humans and rodents. Recent studies in humans and rodents ha
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ve demonstrated that addiction to fats shares a common mechanism with addiction to alcohol, nicotine and narcotics in terms of a dysfunction of brain reward systems. It has been highlighted that a high-fat diet (HFD) attenuates dopamine D2 receptor (D2R) signalling in the striatum, a pivotal regulator of the brain reward system, resulting in hedonic overeating. We previously reported that the brown rice-specific bioactive constituent gamma-oryzanol attenuated the preference for an HFD via hypothalamic control. We therefore explored the possibility that gamma-oryzanol would modulate functioning of the brain reward system in mice.\nMethods Male C57BL/6J mice fed an HFD were orally treated with gamma-oryzanol, and striatal levels of molecules involved in D2R signalling were evaluated. The impact of gamma-oryzanol on DNA methylation of the D2R promoter and subsequent changes in preferences for dietary fat was examined. In addition, the effects of 5-aza-2'-deoxycytidine, a potent inhibitor of DNA methyltransferases (DNMTs), on food preference, D2R signalling and the levels of DNMTs in the striatum were investigated. The inhibitory effects of gamma-oryzanol on the activity of DNMTs were enzymatically evaluated in vitro.\nResults In striatum from mice fed an HFD, the production of D2Rs was decreased via an increase in DNA methylation of the promoter region of the D2R. Oral administration of gamma-oryzanol decreased the expression and activity of DNMTs, thereby restoring the level of D2Rs in the striatum. Pharmacological inhibition of DNMTs by 5-aza-2'-deoxycytidine also ameliorated the preference for dietary fat. Consistent with these findings, enzymatic in vitro assays demonstrated that gamma-oryzanol inhibited the activity of DNMTs.\nConclusions/interpretation We demonstrated that gamma-oryzanol ameliorates HFD-induced DNA hypermethylation of the promoter region of D2R in the striatum of mice. Our experimental paradigm highlights gamma-oryzanol as a promising antiobesity substance with the distinct property of being a novel epigenetic modulator.
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| 6.
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要, 匡 ; 成富, 研二 ; 柳, 久美子 ; Kaname, Tadashi ; Naritomi, Kenji ; Yanagi, Kumiko
概要:
科研費番号: 17590289
平成17年度～平成18年度科学研究費補助金(基盤研究(C))研究成果報告書 研究概要:＜多様なミニ染色体ベクターの作製＞ミニ染色体上のテロメア側、セントロメア内、中間領域での遺伝子発現およ … び染色体の安定性を検討するため、それぞれの領域にゲノム遺伝子(BAC)を導入できるミニ染色体を個別に作製し、検討した。ミニ染色体の改変は、DT40細胞内で行った。1)ミニ染色体改変用プラスミドベクターの構築ヒトX染色体由来ミニ染色体(IKNFA3)の各部位へ、相同組換えにより変異型lox71を挿入するためのプラスミドベクターを作製した。変異型 lox71挿入用ベクターは、blasticidin R発現カセット(CAG lox71 bsr)を用いて作製した。また、ミニ染色体テロメア側の薬剤耐性遺伝子(neoR)をZeocinR遺伝子へ変更するためのtelomere- targeting vectorも新たに作製した。2)ミニ染色体の改変上記挿入用ベクターを用い、ミニ染色体の各部位へCAG lox71 bsrをそれぞれ挿入した改変ミニ染色体を作製した。同時に、テロメア側(短腕側)をZerocinR遺伝子へ変更した。3)改変ミニ染色体へのBAC導入上記改変ミニ染色体へ、遺伝子発現ユニットをもつBAC(HPRT-66, F9-66)をCre/変異lox系を用いて導入した。導入効率は、約70～75％であった。＜BAC導入ミニ染色体における遺伝子発現と安定性＞改変ミニ染色体のテロメア側、セントロメア側、中間領域のそれぞれの領域に挿入されたBAC内遺伝子(HPRT)の発現について検討した。定量PCRによる発現比較では、テロメア側にBACを挿入したクローンのヒトHPRT遺伝子発現を100とすると、セントロメア側挿入クローンでは83、中間領域挿入クローンでは122であった。細胞核あたりのコピー数は、1コピー(約70％)または2コピー(約30％)がほとんどであった。また、内在性Hprt遺伝子発現量に対し、ヒトHPRT遺伝子発現量は約15％であった。これは、宿主細胞の種の違いによると考えられた。長期培養による遺伝子発現は、テロメア側、中間領域挿入クローンで大きな変化はなかった。 要約(欧文):In order to know the position effect and stability of gene expression at various regions in human artificial minichromosomes, we have constructed four types of modified minichromosomes, which was introduced a BAC harboring a whole gene unit (HPRT, or Factor IX) into various sites such as near telomere, near centromere, and euchromatic region, and we investigated intensity and stability of the gene expression. Fist, we constructed plasmid vectors, which could introduce lox71 (mutant loxp) into the human minichromosome at various sites by homologous recombination or telomere targeting method. We also constructed a telomere-targeting vector, which could replace the neoR gene to the ZeoR gene located at the telomeric region in the minichromosome. Then, we modified the minichromosome using the vectors above, and introduced a BAC (HPRT-66 or F9-66) into the modified minichromosomes by the Cre/mutant lox recombination system. The efficiencies of BAC introduction into the minichromoscmes were approximately 75% and 70% for HPRT-66 BAC and F9-66 BAC, respectively. Relative gene expressions of human HPRT gene estimated by qPCR were 100, 83, and 122, when the gene was located near telomere near centromere, and euchromatic region, respectively. Copy number of the modified minichromosomes in DT40 cells was 1 copy/nucleus (approximately 70%) or 2 copies/nucleus (approximately 30%). Relative expression of the human HPRT gene was 15% of authentic Hprt gene expression in DT40. The gene expression was not significantly changed in any modified minichromosomes after 60 days culture. 未公開：P.14以降(別刷論文のため) 研究報告書 続きを見る |
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| 7.
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論文（リポジトリ）
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要, 匡 ; 成富, 研二 ; 柳, 久美子 ; Kaname, Tadashi ; Naritomi, Kenji ; Yanagi, Kumiko
概要:
科研費番号: 15590293
平成15年度～平成16年度科学研究費補助金(基盤研究(C)(2))研究成果報告書 研究概要:＜ミニ染色体改変システムの構築,検証と応用＞ 1)BAC(細菌人工染色体)導入システムの構築と検 … 証テロメア断片化ベクターにより作製された約2.7MbのヒトX染色体由来ミニ染色体に、さらに改変を加え、反応方向特異性をもつ部位特異的組換え系 (Cre/変異loxP)を用いたBAC導入システムを構築した。導入用BACには、作製済みベクターを用いた(Kaname and Huxley, BioTechniques 31:273(2001))。ヒトHPRT遺伝子を含む改変BAC(HPRTBAC66D2)をミニ染色体へ導入した場合の挿入効率は約75％であった。他のBAC(ヒトFactor IX遺伝子を含むF9BAC66D2)においても、効率は同程度(約80％)であった。一方、ネオマイシン耐性遺伝子発現ユニットのみをもつプラスミド (4.5kb)の挿入効率は、100％と非常に高率であった。ヒトHPRT遺伝子を挿入したミニ染色体は、これを保持しているニワトリpre-B細胞株 (DT40)において、遺伝子発現が認められた。よって、このシステムは、遺伝子全体をミニ染色体に挿入するシステムとして、有効であることが示された。(投稿中) 2)染色体ベクターとしての応用改変(挿入)を行ったミニ染色体の、宿主細胞であるDT40から他の細胞への移入を行った。ヒトHPRT遺伝子をもつミニ染色体を微小核融合法により、線維肉腫細胞亜株(HT1080,HPRT(-))へ移入した。G418耐性を指標にクローン (HT1080,HPRT(-))を検討したところ、ミニ染色体は、細胞あたりのコピー数に変動が見られる(1～8コピー)ものの、安定に存在していた。また、HPRT遺伝子発現も効率よく認められた。よって、このミニ染色体は、遺伝子導入のための染色体ベクターとして有効であると考えられた。 要約(欧文):We have established an efficient system for introducing a whole BAC clone including an intact gene unit onto a minichromosome based on the human X chromosome. The use of mutant loxP sites with Cre recombinase and direct selection for the retrofitting event led to a high efficiency of correctly retrofitted clones. A modified BAC containing the intact human HPRT gene was correctly retrofitted onto the minichromosome in DT40 cells in approximately 75% of analysed clones. Modification of BACs for retrofitting was used method previously reported (Kaname and Huxley, BioTechniques 31:273(2001)). For another BAC clone containing human factor IX gene, the efficiency of retrofitting was about 80%. For a plasmid (4.5kb) having a neoR expression unit, the retrofitting efficiency was 100%. The HPRT gene is expressed from the minichromosome at approximately the same level in both of these clones. This system allows one to introduce any gene or gene cluster which can be cloned as a BAC into the minichromosome for gene delivery. We also tried to transfer the modified minichromosomes into other cells (HT1080,HPRT(-)) by microcell-fusion method. It was efficient to isolate the transchromosomic cells by screening of G418 resistant clones. Of the resistant clones, copy number of the minichromosome per cell was in range of 1-8. Its expression was, however, efficient and stable. Thus, the minichromosome would be used as a chromosome vector for gene therapy. 未公開：P.9以降(別刷論文のため) 研究報告書 続きを見る |
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| 8.
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Yanagi, Kumiko ; Kaname, Tadashi ; Chinen, Yasutsugu ; Naritomi, Kenji
概要:
Faciogenital dysplasia 1 (FGD1) gene has been identified as a responsible gene for Aarskog-Scott syndrome (AAS). We char
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acterized two novel point mutations in two Japanese families with AAS, a missense mutation in exon 11 (1906C>T, R636W) and a nucleotide transition at the first position of the 5' splice donor site of intron 14 (IVS14+1G>A). The missense mutation probably results in reduced FGD1 function and the mutation at the splice donor site decreases FGDl gene expression. These mutations were identified by sequencing and were confirmed by allele-specific polymerase chain reaction (AS-PCR) or by PCR-restriction fragment length polymorphism (PCR-RFLP). The mutations were absent in twenty-five Japanese control subjects, which supports the notion that these mutations result in AAS. This study represents the first mutational analysis of FGD1 in Japanese AAS patients.
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