ペルオキシソーム欠損症の発症と温度感受性との関連についての研究

• 研究課題/領域番号: 10670721
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 小児科学
• 研究機関: 岐阜大学
• 研究代表者: 下澤 伸行 (下澤 信行) 岐阜大学, 医学部・附属病院, 講師 (00240797)
• 研究分担者: 鈴木 康之 岐阜大学, 医学部, 助教授 (00163014)
• 研究期間 (年度): 1998 – 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 2,900千円 (直接経費: 2,900千円); 1999年度: 1,300千円 (直接経費: 1,300千円); 1998年度: 1,600千円 (直接経費: 1,600千円)
• キーワード: ペルオキシソーム / Zellweger症候群 / 相補性群 / 温度感受性 / タンパク細胞内輸送 / 新生児型adrenoleukodystrophy / PEX遺伝子

研究概要

ペルオキシソーム欠損症は蛋白のペルオキシソームへの細胞内輸送や膜形成の異常に基づく常染色体劣性の遺伝病で、平成10、11年度の本科学研究により申請者は以下の点を明らかにした。
(1)本症に12個の遺伝的相補性群が存在し、抗ペルオキシソーム膜蛋白抗体を用いた検討より、9群では蛋白のペルオキシソームへの細胞内輸送異常に起因し、残りの3群ではより早期の膜形成過程での異常に起因すると考えられた。
(2)ペルオキシソームが欠損したCHOや酵母のmutantから得られたPEX遺伝子のヒトhomologを患者細胞内に発現させることより3、E、B、D、J群の病因がPEX12、1、10、16、19であることを明らかにし、それぞれの患者変異部位も解析した。
(3)本症の軽症型患者細胞では30℃に培養温度を下げると蛋白がペルオキシソームに正常に局在する温度感受性現象を有することを明らかにし、発現実験より温度感受性変異の存在も明らかにした。
(4)PEX13がH群の病因で、軽症型ではSH3ドメイン内に温度感受性を有するミスセンス変異を有しており、温度による立体構造変化が発症に関わる可能性が示唆された。
(5)臨床像と遺伝子異常との関係として各群に共通して重症型ではナンセンス変異やフレームシフト、軽症型ではミスセンス変異を認め、前者では各蛋白ともほとんどペルオキシソームに輸送されないのに対し、後者では蛋白や細胞ごとにheterogeneityに輸送を認めており、それが残存活性や臨床像の軽症化に相関していた。

研究成果

• [文献書誌] Shimozawa N, et al.: "Genetic basis of peroxisome assembly mutants of humans, CHO cells and yeast"Am J Hum Genet. 63. 1898-1903 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tamura S, Shimozawa N, et al: "Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellweger syndrome of complementation group 1"Proc Natl Aced Sci USA. 95. 4350-4355 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Imamura A, Shimozawa N, et al: "Temperature sensitive phenotypes of peroxisome assembly processes represent the milder torms of human peroxisome biogenesis disorders"Am J Hum Genet. 62. 1539-1543 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Okumoto K, Shimozawa N, et al: "PEX12, the pathogenic gene of group III Zellweger syndrome"Mol Cell Biol. 18. 4324-4336 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shimozawa N, et al.: "Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders"Hum Mol Biol. 8. 1077-1083 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Matsuzono Y, Shimozawa N, et al: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly"Proc Natl Aced Sci USA. 96. 2116-2121 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shimozawa N, Suzuki Y, Zhang Z, Imamura A, Kondo N, Kinoshita N, Fujiki Y, Tsukamoto T, Osumi T, Imanaka T, Orii T, Beemer F, Mooijer P, Dekker C, and Wanders RJA: "Genetic basis of peroxisome assembly mutants of humans, CHO cells and yeast: identification of a new complementation group of peroxisome biogenesis disorders, absent from peroxisomal membrane ghosts."Am J Hum Genet. 63. 1898-1903 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N., Suzuki Y., Tomatsu S., Nakamura H., Kono T., Takada H., Tsukamoto T., Fujiki Y., Orii T., Kondo N.,: "A novel mutation in peroxisome assembly factor-1 responsible for Zellweger syndrome."Human Mutation. Suppl 1. 134-136 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N., Suzuki Y., Zhang Z., Imamura A., Tsukamoto T., Osumi T., Tateishi K., Okumoto K., Fujiki Y., Orii T., Barth PG, Wanders RJA, Kondo N.: "Peroxisome biogenesis disorders: Identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX13."Biochem. Biophys. Res. Commun.. 243. 368-371 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tamura S, Okumoto K, Toyama R, Shimozawa N, Tsukamoto T, Suzuki Y, Osumi T, Kondo N, and Fujiki Y: "Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellwegar syndrome of complementation group I."Proc Natl Acad Sci USA. 95. 4350-4355 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tamura S, Shimozawa N, Suzuki Y, Tsukamoto T, Osumi T, and Fujiki Y: "A cytoplasmic AAA family peroxin, Pex1p, interacts with Pex6p."Biochem Biophys Res Commun. 245. 883-886 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Imamura A, Tsukamoto T, Shimozawa N, Suzuki Y, Zhang Z, Imanaka T, Fujiki Y, Orii T, Kondo N, and Osumi T: "Temperature sensitive phenotypes of peroxisome assembly processes represent the milder forms of human peroxisome biogenesis disorders."Am J Hum Genet. 62. 1539-1543 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kinoshita N, Ghaedi K, Shimozawa N, Wanders RJA, Matsuzono Y, Imanaka T, Okumoto, K, Suzuki Y, Kondo N, and Fujiki Y: "Newly identified chinese hamster ovary cell mutants are defective in biogenesis of peroxisomal membrane vesicles (peroxisomal ghosts), representing a novel complementation group in mammals."J Biol Chem. 273. 24122-24130 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Okumoto K, Shimozawa N, Kawai A, Tamura S, Tsukamoto T, Osumi T, Moser H, Wanders RJA, Suzuki Y, Kondo N, and Fujiki Y: "PEX12, the pathogenic gene of group III Zellweger syndrome: cDNA cloning by functional complementation on a CHO cell mutant, patients analysis, and characterization of Pex12p."Mol Cell Biol. 18. 4324-4336 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Okumoto K, Itoh R, Shimozawa N, Suzuki Y, Tamura S, Kondo N, and Fujiki Y: "Mutation in PEX10 is the cause of Zellweger peroxisome-deficiency syndrome of complementation group B."Hum Mol Genet. 7. 1399-1405 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Honsho M, Tamura S, Shimozawa N, Suzuki Y, Kondo N, and Fujiki Y: "Mutation in PEX16 is causal in the peroxisome-dificient Zellweger syndrome of complementation group D."Am J Hum Genet. 63. 1622-1630 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Imamura A, Tamura S, Shimozawa N, Suzuki Y, Zhang Z, Tsukamoto T, Orii T, Kondo N, Osumi T, and Fujiki Y: "Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders in the highest-incidence group."Hum Mol Genet. 7. 2089-2094 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Fukuda S, Suzuki Y, Shimozawa N, Zhang Z, Orii T, Aoyama T, Hashimoto T, and Kondo N: "Amino acid and nucleotide sequences of human peroxisomal enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase cDNA."J Inher Metab Dis. 21. 23-28 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N, Suzuki Y, Zhang Z, Imamura A, Toyama R, Mukai S, Fujiki Y, Tsukamoto T, Osumi T, Orii T, Wanders RLA, and Kondo N: "Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders."Hum Mol Genet. 8. 1077-1083 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N, Zhang Z, Suzuki Y, Imamura A, Tsukamoto T, Osumi T, Fujiki Y, Orii T, Barth PG, Wanders RJA, and Kondo N: "Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5-defective patients"Biochem Biophys Res Commun. 262. 504-508 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N, Imamura A, Zhang Z, Suzuki Y, Orii T, Tsukamoto T, Osumi T, Fujiki Y, Wanders RJA, Besley GT, and Kondo N: "Defective PEX gene products correlate to the protein import, biochemical abnormalities and phenotypic heterogeneities in peroxisome biogenesis disorders."J Med Genet. 36. 779-781 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N, Suzuki Y, Zhang Z, Miura K, Matsumoto A, Nagaya M, Castillo-Taucher S, and Kondo N: "A novel nonsense mutation of the PEX7 gene in a patient with rhizomelic chondrodysplasia punctata."J Human Genet. 44. 123-125 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Matsuzono Y, Kinoshita N, Tamura S, Shimozawa N, Hamasaki M, Ghaedi K, Wanders RJA, Suzuki Y, Kondo N, and Fujiki Y: "Human PEX19: cDNA cloning by functional complementation, mutation analysis in a patient with Zellweger syndrome, and potential role in peroxisomal membrane assembly."Proc Natl Acad Sci. 96. 2116-2121 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Zhang Z, Suzuki Y, Shimozawa N, Fukuda S, Imamura A, Tsukamoto T, Osumi T, Fujiki Y, Orii T, Wanders RJA, Barth PG, Moser HW, Paton BC, Besley GT, and Kondo N: "Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders"Hum Mut. 13. 487-496 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Wanders RJA, Mooijer PA, Dekker C, Suzuki Y, and Shimozawa N: "Disorders of peroxisome biogenesis: complementation analysis shaws genetic heterogeneity with strong overrepresentation of one group"J Inherit Metan Dis. 22. 314-318 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Suzuki Y, Zhang Z, Shimozawa N, Muro M, Shono H, Toda S, Miyahara S, Hashimoto T, Usuda N, Ito M, Takashima S, and Kondo N: "Prenatal diagnosis of peroxisomal D-3-hydroxyacyl-CoA dehydratase/ D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein deficiency."J Human Genet. 44. 143-147 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ghaedi K, Kawai A, Okumoto K, Tamura S, Shimozawa N, Suzuki Y, Kondo N, and Fujiki Y: "Isolation and characterization of novel peroxisome biogenesis-defective Chinese hamster ovary cell mutants using green fluorescent protein"Exp Cell Res. 248. 489-497 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ghaedi K, Itagaki A, Toyama R, Tamura S, Matsumura T, Kawai A, Shimozawa N, Suzuki Y, Kondo N, and Fujiki Y: "Newly identified Chinese hamster ovary cell mutants defective in peroxisome assembly represent complementation group A of human peroxisome biogenesis disordersand one novel group in mammals"Exp Cell Res. 248. 482-488 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Yamada T, Taniwaki T, Shinnoh N, Uchiyama A, Shimozawa N, Ohyagi Y, Asahara H, and Kira J: "Adrenoleukodystrophy protein enhances association of very long-chain acyl-coenzyme A synthetase with the peroxisome"Neurology. 52. 614-616 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Saito M, Iwamori M, Lin B, Oka A, Fujiki Y, Shimozawa N, Kamoshita S, Yanagisawa M, and Sakakihara Y: "Accumulation of glycolipids in mutant Chinese hamster ovary cells (Z65) with defective peroxisomal assembly and comparison of the metabolic rate of glycosphingolipids between Z65 cells and wild-type CHO-K1 cells"Biochim Biophys Acta. 1438. 55-62 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Zhang Z, Suzuki Y, Shimozawa N, Kawabata I, Tamaya T, Sato K, and Kondo N: "Prenatal diagnosis of peroxisome biogenesis disorders by means of immunofluorescence staining of cultured chorionic villous cells"Clin Genet. 56. 467-468 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N, Zhang Z, Imamura A, Suzuki Y, Fujiki Y, Tsukamoto T, Osumi T, Aubourg P, Wanders RJA, and Kondo N: "Molecular mechanism of detectable catalase-containing particles, peroxisomes in fibroblasts from PEX2 defective patient"Biochem Biophys Res Commun. (in press).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimozawa N,et al.: "Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders"Hum Mol Genet. 8. 1077-1083 (1999)
• [文献書誌] Shimozawa N,et al.: "Functional heterogeneity of C-terminal peroxisome targeting signal 1 in PEX5・detective patients"Biochem Biophys Res Commun. 262. 504-508 (1999)
• [文献書誌] Shimozawa N,et al.: "Defective PEX gene products correlate to the protein inport, biochemical abnormalities and phenotyic hetero geneitiesin peroxisome biogenesis disorders"J Med Genet. 36. 779-781 (1999)
• [文献書誌] Shimozawa N,et al.: "A novel nonsense mutation of the.PEX7 gene in a patient with rhizomelic chondrody splasia punctata"J Hom Genet. 44. 123-125 (1999)
• [文献書誌] Matsuzono Y,Shimozawa N,et al.: "Human PEX19:cDNA cloning by functional complementation,mutation analysis with Zellweger syndrome, and potential role in peroxisomal membrane assembly"Proc Natl Acad Sci. 96. 2116-2121 (1999)
• [文献書誌] Shimozawa N,et al.: "Molecular mechanism of detectable catalase-containing particles,peroxisome in tibroblasts from PEX2 detective patient"Biochem Biophys Res Commun. (in press). (2000)
• [文献書誌] N,Shimozawa et al: "Genetic basis of peroxisome assembly mutants of humans,CHO cells and yeast : Identification of anew coinpleuertation group of peroxisoine biogmesis dissorodivs" Am,J Hum Genet. 63. 1898-1903 (1998)
• [文献書誌] M.Honsho,N.Shimozawa et al: "Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D" Am J Hum Genet. 63. 1622-1630 (1998)
• [文献書誌] A.Imamura,N.Shimozawa et al: "Temperature-sensitive mutation in PEX1 moderates the phenotypes of peroxisome deficiency disorders" Hom Mol Genet. 7. 2089-2094 (1998)
• [文献書誌] A.Imamura,N.Shimozawa et al: "Temperature-sensitive phenotypes of peroxisome-assembly processes represent the milder forms of human peroxisome-biogenesis disorders" Am J Hom Genet. 62. 1539-1543 (1998)
• [文献書誌] K.Okumoto,N.Shimozawa et al: "PEX12,the pathogenic gene of group III Zellweger syndrome" Mol Cell Biol. 18. 4324-4336 (1998)
• [文献書誌] S.Tamura,N.Shimozawa et al: "Human PEX1 cloned by tunctional complementation on a CHO cell mutant is responsible for peroxisome deficient Zellweger syndrome of complementation group I" Proc Natl Acad Sci USA. 95. 4350-4355 (1998)