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.

这项研究是鉴定引起各种人的疾病基因 骨骼发育不良，并识别已确定的 突变和由此产生的表型。研究的疾病包括但 不限于pycnodysostosis，Ellis-Van Crevald（EVC）综合征， Brachydactyly型C和II型胶原蛋白疾病。皮肤病性造生造成病 - 连续研究包括对组织蛋白酶活性的分析 受影响患者的巨噬细胞以及分子分析 组织蛋白酶K基因用于新突变。 Ellis-Van Crevald综合征。去 研究，与M. Polymeropoulos和M. Burn合作，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。 Brachydactyly类型C。进一步 连锁研究和位置候选基因分析正在进行中 对于此表型。 II型胶原蛋白混乱。我们使用了杂波 分析以识别4个患有膝盖的人的序列异常 发育不良。检验基因组DNA的测序鉴定了三个新的 COL2A1中的主要突变，导致膝盖异常增生：21BP 外显子16中的删除，外显子19中的18 bp删除和4 bp删除 内含子14和20的剪接供体位点。先前描述的 在第四概率中确定了膝盖突变。这个突变是一个 COL2A1外显子12/内含子12交界处的28BP删除，删除 剪接供体网站。这些数据表明膝盖发育不良主要 较短的II型胶原蛋白单体的结果，并支持 假设可能跨越COL2A1外显子的域的改变 12-24，导致最新的表型。