MOLECULAR GENETICS OF HUMAN SKELETAL DYSPLASIAS

人类骨骼发育不良的分子遗传学

• 批准号: 6162542
• 负责人: C A FRANCOMANO
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162542
• 关键词: adolescence (12-20); child (0-11); clinical research; congenital skeletal disorder; family genetics; gene expression; genetic disorder; genetic markers; genetic polymorphism; genotype; human genetic material tag; human tissue; linkage mapping; molecular genetics; phenotype

This study is to identify disease genes causing a variety of human skeletal dysplasias, and to identify relationships between the identified mutations and the resulting phenotypes. Disorders studied include, but are not limited to, pycnodysostosis, Ellis-van Crevald (EvC) syndrome, Brachydactyly type C and the type II collagen disorders. Pycnodysostosis -continuing studies include analysis of cathepsin K activity in the macrophage from affected patients, as well as molecular analysis of the cathepsin K gene for new mutations. Ellis-van Crevald syndrome. On going studies, in collaboration with M. Polymeropoulos and M. Burn, include exon trapping in the EvC candidate interval, positional candidate gene analysis, and cDNA selection studies. Brachydactyly type C. Further linkage studies and positional candidate gene analysis are in progress for this phenotype. Type II collagen disordera. We used heteroduplex analysis to identify sequence anomalies in 4 individuals with Kniest dysplasia. Sequencing of the probands' genomic DNA identified three new dominant mutations in COL2A1 which result in Kniest dysplasia: a 21bp deletion in exon 16, a 18 bp deletion in exon 19, and 4 bp deletions in the splice donor sites of introns 14 and 20. A previously described Kniest mutation was identified in a fourth proband. This mutation was a 28bp deletion at the COL2A1 exon 12/intron 12 junction, deleting the splice donor site. These data suggest that Kniest dysplasia predominately results from shorter type II collagen monomers, and support the hypothesis that alteration of a domain, which may span from COL2A1 exons 12-24, leads to the Kniest phenotype.

这项研究是为了确定引起各种人类疾病的基因， 骨骼发育不良，并确定之间的关系，确定 突变和由此产生的表型。研究的疾病包括，但 不限于，致密性成骨不全，Ellis-van Crevald（EvC）综合征， C型短指（趾）畸形和II型胶原紊乱。密结性成骨不全 - 继续的研究包括分析组织蛋白酶K活性， 巨噬细胞，以及分子分析， 组织蛋白酶K基因的新突变。Ellis-van Crevald综合征要去 研究，与M。Polymeropoulos和M.燃烧，包括 EvC候选间隔中的外显子捕获，位置候选基因 分析和cDNA选择研究。C型短指畸形进一步 连锁研究和定位候选基因分析正在进行中 for this phenotype表型. II型胶原紊乱a。我们用异源双链 分析，以确定4个个体中的序列异常， 发育不良先证者的基因组DNA测序确定了三个新的 COL 2A 1的显性突变导致最严重的发育不良：一个21 bp的 外显子16缺失，外显子19缺失18 bp，外显子16缺失4 bp。 内含子14和20的剪接供体位点。先前描述的 第四个先证者发现了最大的突变。这种突变是一种 COL 2A 1外显子12/内含子12连接处28 bp缺失，缺失了 剪接供体位点。这些数据表明，最大的发育不良主要是 结果从较短的II型胶原蛋白单体，并支持 假设一个结构域改变，其可能跨越COL 2A 1外显子 12-24，导致最大的表型。