Genetic analysis and diagnosis of skeletal dysplasias

骨骼发育不良的遗传分析与诊断

• 批准号: 11470300
• 负责人: IKEGAWA Shiro
• 金额: $ 9.22万
• 依托单位: SNP Research Center, RIKEN (2000)The University of Tokyo (1999)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470300/
• 关键词: Skeletal dysplasia; gene; diagnosis; disease gene; genome; cloning; bone; cartilage

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. Isolation of a candidate gene for Shwachman syndromeI analyzed a de novo reciprocal translocation, (t(6 ; 12)(q16.2 ; q21.2)) associated with Shwachman syndrome. I cloned the translocation breakpoints and determined the DNA sequences. I identified a gene that is disrupted by the breakpoint, a candidate gene for Shwachman syndrome.2. Isolation of novel candidate genesThrough in silico cloning, I cloned novel candidate genes for skeletal dysplasias, ASH2L (ash2-like), PROSC (proline synthetase co-transcribed), C8orf2, CILP (cartilage intermediate layer protein), PRG4 (proteoglycan 4). I determined genomic structure and chromosomal localization of the genes, and analyzed their expression.3. Identification of a candidate gene for Engelamnn diseaseIn collaboration with Prof.Niikawa's group by a positional candidate gene approach, I found the disease gene for Engelmann disease is TGF-beta1.4. Mutation analysis of EBP gene in X-linked dominant chondrodysplasia punctataI identified 5 novel mutations of the EBP (emopamil-binding protein) gene in X-linked dominant chondrodysplasia punctata ; three of them were nonsense and two missense mutations. I found the enzyme activity of EBP in the patients correlated well with the genotype.

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。Shwachman综合征候选基因的分离我分析了与Shwachman综合征相关的从头互惠易位(t（6; 12)(q16.2; q21.2)）。我克隆了易位断点并确定了DNA序列。我发现了一个被断点破坏的基因，这是什瓦赫曼综合征的候选基因。新候选基因的分离通过硅克隆，我克隆了新的骨骼发育不良候选基因，ASH2L （ash2样），PROSC（脯氨酸合成酶共转录），C8orf2， CILP（软骨中间层蛋白），PRG4（蛋白多糖4）。我确定了基因的基因组结构和染色体定位，并分析了它们的表达。通过与niikawa教授的团队合作，通过定位候选基因的方法，我发现了Engelmann病的致病基因是TGF-beta1.4。x -连锁显性点状软骨发育不良患者EBP基因突变分析在x -连锁显性点状软骨发育不良患者中发现了5个新的EBP基因突变；其中三个是无义突变，两个是错义突变。我发现患者的EBP酶活性与基因型有很好的相关性。

项目成果

Ikegawa S, Isomura M, Koshizuka Y, Nakamura Y.: "Cloning and characerization of ASH2L and Ash2l, human and mouse homologs of the Drosophila ash2 gene."Cytogenet Cell Genet. 84. 167-172 (1999)

Ikekawa S、Isomura M、Koshizuka Y、Nakamura Y.：“果蝇 ash2 基因的人类和小鼠同源物 ASH2L 和 Ash2l 的克隆和表征。”Cytogenet Cell Genet。

Nishimura G,Ikegawa S,Saga T,Nagai T,Aya M,Kawano T.: "Metaphyseal anadysplasia : evidence of genetic heterogeneity." Am J Med Genet. 82 (1). 43-48 (1999)

Nishimura G，Ikekawa S，Saga T，Nagai T，Aya M，Kawano T.：“干骺端发育不良：遗传异质性的证据。”

Makita Y, Nishimura G, Ikegawa S, Ishii T, Ito Y.: "Okuno Alntrafamilial phenotypic variability in engelmann disease (ED) : are ED and Ribbing disease the same entity?"Am J Med Genet. 91(2). 153-6 (2000)

Makita Y、Nishimura G、Ikekawa S、Ishii T、Ito Y.：“恩格曼病 (ED) 的 Okuno Alntrafamilial 表型变异：ED 和 Ribbing 病是同一实体吗？”Am J Med Genet。

Shiro Ikegawa: "Cloning and characterization of ASH2L and Ash21,human and mouse homelogs of the Drosophila ash2 gene"Cytogenetics and Cell Genetics. 84(3-4). 167-172 (1999)

Shiro Ikekawa：“果蝇 ash2 基因的人类和小鼠同系物 ASH2L 和 Ash21 的克隆和表征”细胞遗传学和细胞遗传学。

Ikegawa S, Masuno M, Kumano Y, Okawa A, Isomura M, Koyama K, Okui K, Makita Y, Sasaki M, Kohdera U, Okuda M, Koyama H, Ohashi H, Tajin H, Imaizumi K, Nakamura Y.: "Cloning of translocation breakpoints associated with Shwachman syndrome and identification

池川 S、增野 M、熊野 Y、大川 A、矶村 M、小山 K、奥井 K、牧田 Y、佐佐木 M、小寺 U、奥田 M、小山 H、大桥 H、Tajin H、今泉 K、中村 Y："