骨系統疾患の疾患遺伝子の解析

• 研究課題/領域番号: 14370476
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 整形外科学
• 研究機関: 独立行政法人理化学研究所
• 研究代表者: 池川 志郎 独立行政法人理化学研究所, 変形性関節症関連遺伝子研究チーム, チームリーダー (30272496)
• 研究期間 (年度): 2002 – 2003
• 研究課題ステータス: 完了 (2003年度)
• 配分額: 13,300千円 (直接経費: 13,300千円); 2003年度: 6,400千円 (直接経費: 6,400千円); 2002年度: 6,900千円 (直接経費: 6,900千円)
• キーワード: 遺伝子診断 / 骨系統疾患 / 骨・関節疾患 / 遺伝子変異 / pseudoachondroplasia / MED / COMP遺伝子 / COL2A1遺伝子 / pseudochondroplasia / 疾患遺伝子 / 遺伝子解析 / 遺伝子

研究概要

遺伝子レベルでの骨系統疾患(骨・関節の遺伝子病)の診断方法を確立し、同定した遺伝子変異について臨床像と遺伝子型との関連を検討し、骨系統疾患の病態を明らかにすることを目的として研究を行ない、本年度は以下のような成果を得た。
1,platyspondylic skeletal dysplasia, Torrance typeの原因遺伝子がCOL2A1遺伝子であることを発見した。
2,以下の疾患、遺伝子において新規の遺伝子変異を同定した。
(1)pseudoachondroplasia、multiple epiphyseal dysplasia (MED)におけるCOMP遺伝子
(2)Hypochondrogenesis、Spondyloepiphyseal dysplasia congenita、Kniest dysplasia、Stickler症候群、Spondyloepiphyseal dysplasia tardaにおけるCOL2A1遺伝子
(3)MEDにおけるMATN3遺伝子
(4)MEDにおけるCOL9A3遺伝子
(5)Cartilage-Hair hypoplasiaにおけるRMRP遺伝子
(6)Camurati-EngelmannにおけるTGFB1遺伝子
(7)Shwachman-Diamond症候群におけるSBDS遺伝子
3,COMPの変異を持つpseudoachondroplasiaとMEDの患者では、血清COMPが低下していることを発見した。これにより、MEDの遺伝的異質性の簡単なスクリーニングが可能となり、効率的遺伝子診断が行える事が明らかになった。

研究成果

• [文献書誌] Nishimura Gen: "Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form : Clinical course and phenotypic variations in four patients."American Journal of Medical Genetics. 117A(2). 147-153 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Matsuyama Juntaro: "A pair of sibs with tibial hemimelia horn to phenotypically normal parents."Journal of Human Genetics. 48(4). 173-176 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishimura Gen: "Spondyloepiphyseal dysplasia Maroteaux type : Report of three patients from two families and exclusion of type II collagen defects."American Journal of Medical Genetics. 120A(4). 498-502 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nakashima Eiji: "S. RMRP Mutations in Japanese Patients with Cartilage-Hair Hypoplasia."American Journal of Medical Genetics. 123A(3). 253-256 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ikegawa Shiro: "Allele specific PCR amplification due to sequence identify between a PCR primer and an amplicon : Is direct sequencing so reliable?"Human Genetics. 110(6). 606-608 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishimura Gen: "Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form : Clinical course and phenotypic variations in four patients."American Journal of Medical Genetics. 107(1). 5-11 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kawaji Hiroyuki: "Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein(COMP)gene : further expansion of the phenotypic variations of COMP"Skeletal Radiology. 31(12). 703-707 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Shirahama Shuya: "Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata."Human Genetics. 112(1). 78-83 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mabuchi Akihiko: "Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia."Human Genetics. 112(1). 84-90 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nicola Brunetti-Pierri: "A new patient with Lowry-Wood syndrome with mild phenotype."American Journal of Medical Genetics. 118A(1). 68-70 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nishimura Gen: "Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type."Journal of Medical genetics. 41(1). 75-79 (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nakashima Eiji: "Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome."Human Genetics. 114(4). 345-348 (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kinoshita Akira: "TGFB1 mutations in four new families with Camurati-Engelmann disease : Confirmation of independently arising LAP-domain-specific mutations."American Journal of Medical Genetics. (In press). (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mabuchi Akihiko: "COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COM mutations."American Journal of Medical Genetics. (In press). (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ikegawa Shiro: "Correspondence-Hypomorphic alleles within the EBP gene cause a henotype quite different from Conradi-Hunermann-Happle syndrome."American Journal of Medical Genetics. (In press). (2004)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ikegawa S, Mabuchi A, Ogawa M, Ikeda T.: "Allele specific PCR amplification due to sequence identity between a PCR primer and an amplicon : Is direct sequencing so reliable?"Hum Genet. 110(6). 606-608 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimura C, Nishimura H, Tanaka Y, Makita Y, Ikegawa S, Ghadami M, Kinoshita A, Niikawa N.: "Camurati-Engelmann disease type II. Progressive diaphyseal dysplasia with striations of the bones."Am J Med Genet. 107(1). 5-11 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kawaji H, Nishimura G, Watanabe S, Mabuchi A, Ikeda T, Ohashi H, Sasaki A, Sano T, Ikegawa S.: "Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein (COMP) gene : further expansion of the phenotypic variations of COMP defects."Skeletal Radiol. 31(12). 730-737 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shirahama S, Miyahara A, Kitoh H, Honda A, Kawase A, Yamada K, Mabuchi A, Kura H, Yokoyama Y, Tsutsumi M, Ikeda T, Tanaka N, Nishimura G, Ohashi H, Ikegawa S.: "Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata."Hum Genet. 112(1). 78-83 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mabuchi A, Manabe N, Haga N, Kitoh H, Ikeda T, Kawaji H, Tamai K, Hamada J, Nakamura S, Brunetti-Pierri N, Kimizuka M, Takatori Y, Nakamura K, Nishimura G, Ohashi H, Ikegawa S.: "Novel types of COMP mutations and genotype-phenotype associtation in pseudoachondroplasia and multiple epiphyseal dysplasia."Hum Genet. 112(1). 84-90 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimura G, Honma T, Shiihara T, Manabe N, Nakajima E, Adachi M, Mikawa M, Fukushima Y, Ikegawa S.: "Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form : Clinical course and phenotypic variations in four patients."Am J Med Genet. 117A(2). 147-153 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Brunetti-Pierri N, De Brasi D, Ikegawa S, Camera G, Andria G, Sebastio G.: "A new patient with Lowry-Wood syndrome with mild phenotype."Am J Med Genet. 118A(1). 68-70 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ikeda T, Matsuyama J, Mabuchi A, Zhang J, Iida A, Kimizuka M, Ikegawa S.: "A pair of sibs with tibial hemimelia born to phenotypically normal parents."J Hum Genet. 48(4). 173-176 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimura G, Kizu R, Kijima Y, Sakai K, Kawaguchi Y, Kimura T, Matsushita I, Shirahama S, Ikeda T, Ikegawa S, Hasegawa T.: "Spondyloepiphyseal dysplasia Maroteaux type : Report of three patients from two families and exclusion of type II collagen defects."Am J Med Genet. 120A(4). 498-502 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nakashima E, Mabuchi A, Kashimada K, Onishi, T, Zhang J, Ohashi H, Nishimura G, Ikegawa S.: "RMRP Mutations in Japanese Patients with Cartilage-Hair Hypoplasia."Am J Med Genet. 123A(3). 253-256 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimura G, Nakashima B, Mabuchi A, Shimamoto K, Shimamoto T, Shimao Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S.: "Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type."J Med Genet. 41(1). 75-79 (2004)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nakashima B, Mabuchi A, Makita, Ohashi H, Nishimura G, Ikegawa S.: "Novel SBDS Mutations Caused by Gene Conversion in Japanese Patients with Shwachman-Diamond Syndrome."Hum Genet. 114(4). 345-348 (2004)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kinoshita A, Shirahama 5, Miyahara S, Haga N, Namba A, Ueda H, Hayashi H, Seidel J, Fukumaki Y, Yoshiura K, Ikegawa S, Niikawa N.: "TGFBI mutations in four new families with Camurati-Engelmann disease : Confirmation of independently arising LAP-domain-specific mutations."Am J Med Genet. (in press).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Mabuchi A, Momohara S, Haga N, Ohashi H, Takatori Y, Nishimura G, Ikegawa S.: "Circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations."Am J Med Genet. (in press).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ikegawa S.: "Correspondence-Hypomorphic alleles within the EBP gene cause a phenotype quite different from Conradi-Hunermann-Happle syndrome."Am J Med Genet. (in press).
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nishimura Gen: "Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form : Clinical course and phenotypic variations in four patients."American Journal of Medical Genetics. 117A(2). 147-153 (2003)
• [文献書誌] Matsuyama Juntaro: "A pair of sibs with tibial hemimelia born to phenotypically normal parents."Journal of Human Genetics. 48(4). 173-176 (2003)
• [文献書誌] Nishimura Gen: "Spondyloepiphyseal dysplasia Maroteaux type : Report of three patients from two families and exclusion of type II collagen defects."American Journal of Medical Genetics. 120A(4). 498-502 (2003)
• [文献書誌] Ikegawa Shiro: "Genetic analysis of osteoarthritis : toward identification of its susceptibility genes."Journal of Orthopaedic Science. 8(5). 737-739 (2003)
• [文献書誌] Nakashima Eiji: "S. RMRP Mutations in Japanese Patients with Cartilage-Hair Hypoplasia."American Journal of Medical Genetics. 123A(3). 253-256 (2003)
• [文献書誌] Ikegawa Shiro: "Allele specific PCR amplification due to sequence identity between a PCR primer and an amplicon : Is direct sequencing so reliable?"Human Genetics. 110(6). 606-608 (2002)
• [文献書誌] Ikeda Toshiyuki: "Identification and characterization of the human long form of Sox5 (L-SoX5) gene"Gene. 298(1). 59-68 (2002)
• [文献書誌] Kawaji Hiroyuki: "Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein (COMP) gene : further expansion of the phenotypic variations of COMP defects"Skeletal Radiology. 12. 730-737 (2002)
• [文献書誌] Shirahanma Shyuya: "Skewed X-chromosome inactivation causes intra-familial phenotypicvariation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata"Human Genetics. 112(1). 78-83 (2003)
• [文献書誌] Mabuchi Akihiko: "Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia"Human Genetics. 112(1). 84-90 (2003)