Analysis of disease genes for skeletal dysplasias

骨骼发育不良疾病基因分析

• 批准号: 14370476
• 负责人: IKEGAWA Shiro
• 金额: $ 8.51万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370476/
• 关键词: genetic diagnosis; skeletal dysplasia; bone and joint disease; mutation; pseudoachondroplasia; MED; COMP; COL2A1; pseudochondroplasia; 疾患遺伝子; 遺伝子解析; 遺伝子

To establish a system for DNA diagnosis of skeletal dysplasias, genetic disorders of bone and cartilage, and gain insight for their pathogenesis, I performed genetic analysis of skeletal dysplasias and obtained the following results.1.Direct sequencing is not always reliable. Allele specific PCR amplification could occur due to sequence identity between a PCR primer and an amplicon.2.We identified 3 novel EBP mutations in X-linked dominant chondrodysplasia punctata and found skewed X-chromosome inactivation causes intra-familial phenotypic variation.(1)We identified 9 novel COMP mutations in pseudoachondroplasia and MED (multiple epiphyseal dysplasia) and genotype-phenotype association.(2)We identified for the first time that platyspondylic skeletal dysplasia, Torrance type is caused by COL2A1 mutation.(3)We found novel mutations in the following disease:(4)COL2A 1 in hypochondrogenesis、 spondyloepiphyseal dysplasia congenita、 Kniest dysplasia、Stickler syndrome and spondyloepiphyseal dysplasia tarda.(5)MAIN3 and COL9A3 in MED.(6)RMRP in Cartilage-Hair ].(7)TGFB1 in Camurati-Engelmann disease.(8)SBDS in Shwachman-Diamond syndrome.3.We found circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations.

为了建立骨骼发育不良、骨和软骨遗传疾病的DNA诊断体系，并深入了解其发病机制，我对骨骼发育不良进行了遗传分析，得到以下结果：1。直接测序并不总是可靠的。由于PCR引物和扩增子之间的序列相同，可以发生等位基因特异性PCR扩增。我们在x连锁显性点状软骨发育不良中发现了3个新的EBP突变，并发现扭曲的x染色体失活导致家族内表型变异。(1)我们在假性软骨发育不全和多发性骨骺发育不良（MED）中发现了9个新的COMP突变，并发现了基因型-表型相关性。(2)首次发现Torrance型脊椎病是COL2A1突变所致。(3)我们在以下疾病中发现了新的突变：(4)COL2A - 1在软骨发育不良、先天性脊柱骨骺发育不良、Kniest发育不良、Stickler综合征和迟发性脊柱骨骺发育不良中。(5) MED中的MAIN3和COL9A3。(6)软骨毛中的RMRP。(7)TGFB1在Camurati-Engelmann病中的作用。(8) Shwachman-Diamond综合征的SBDS。我们发现携带COMP突变的假性软骨发育不全和多发性骨骺发育不良患者循环COMP减少。

项目成果

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)

Brunetti-Pierri N、De Brasi D、Ikekawa S、Camera G、Andria G、Sebastio G.：“一名患有轻度表型的 Lowry-Wood 综合征的新患者。”Am J Med Genet。

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.

Nishimura G、Kizu R、Kijima Y、Sakai K、Kawaguchi Y、Kimura T、Matsushita I、Shirahama S、Ikeda T、Ikekawa S、Hasekawa T.：“脊椎骨骺发育不良 Maroteaux 型：来自两个家庭的三名患者的报告和排除

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)

Nishimura Gen：“脊椎骨骺发育不良 Maroteaux 型：来自两个家庭的三名患者的报告并排除 II 型胶原缺陷。”美国医学遗传学杂志。

Nakashima Eiji: "S. RMRP Mutations in Japanese Patients with Cartilage-Hair Hypoplasia."American Journal of Medical Genetics. 123A(3). 253-256 (2003)

Nakashima Eiji：“日本软骨毛发发育不全患者中的 S. RMRP 突变。”美国医学遗传学杂志。

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)

池川四郎：“EBP 基因内的对应亚等位基因导致与 Conradi-Hunermann-Happle 综合征完全不同的表型。”美国医学遗传学杂志。