MOLECULAR GENETICS OF HUMAN SKELETAL DYSPLASIAS

人类骨骼发育不良的分子遗传学

• 批准号: 2576521
• 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/2576521
• 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, nail-patella syndrome, Ellis-van Crevald (EvC) syndrome, Brachydactyly type C, Schmid metaphyseal chondrodysplasia (SMCD), and the type II collagen disorders. Pycnodysostosis - We used linkage analysis to narrow the region of the pycnodysostosis locus to 3cM. Using a positional candidate gene approach, the gene encoding extracellular matrix protein 1 (ECM1) and cathepsin K were analyzed. We have identified cathepsin K as the pycnodysostosis gene. Ellis-van Crevald syndrome - Together with M. Polymeropoulos (LGDR), we have narrowed the region of the EvC gene to roughly 1 cM on chromosome 4p. We have also excluded HOX7 as the EvC gene. Brachydactyly type C was mapped to human chromosome 12 in collaboration with Mihaelis Polymeropoulos, LGDR, NCHGR. Nail-Patella syndrome - Linkage mapping has narrowed the candidate region for the NPS locus to a 1-2 cM interval between markers D9S60 and the adenylate kinase gene on 9q34. SMCD - Three new families have been ascertained. In one family, segregation of a previously unreported nonsense mutation in the NC1 domain of COL10A1 was demonstrated with the SMCD phenotype. In a second family. a tyrosine to histidine mutation in type X collagen has been identified in the proband but co-segregation remains to be proved. In the third family, no mutation has yet to be identified. Type II collagen disorders - We have identified 4 new mutations in individuals with Kniest dysplasia, all of which result in shortened type II collagen fibers. These mutations are all clustered between exons 12 and 24, further adding to the hypothesis that mutations of distinct type and location result in the Kniest phenotype. We have also further clinically and molecularly defined Stickler syndrome families, suggesting the presence of a fourth Stickler gene, and suggesting that the complication of severe visual manifestations may distinguish between families linked to COL2A1 and those due to mutations in other genes.

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 不限于密结性成骨不全、甲-髌骨综合征、Ellis-van Crevald（EvC）综合征，C型短指（趾）畸形，Schmid干骺端 软骨发育不良（SMCD）和II型胶原蛋白紊乱。 密结性成骨不全-我们使用连锁分析来缩小 致密成骨不全基因座为3cM。使用位置候选基因方法， 编码细胞外基质蛋白1（ECM 1）和组织蛋白酶K的基因 分析了我们已经确定组织蛋白酶K为致密型成骨不全症 基因 Ellis-van Crevald综合征-与M. Polymeropoulos（LGDR），我们 已经将EvC基因的区域缩小到染色体上的大约1 cM 4便士。我们还排除了HOX 7作为EvC基因。 C型短指（趾）畸形定位于人类12号染色体 Mihaelis Polymeropoulos，LGDR，NCHGR。 甲-髌综合征-连锁标测缩小了候选区域 将D9 S60和D9 S60之间的间隔调整为1-2 cM， 腺苷酸激酶基因位于9 q34。 SMCD -三个新的家庭已经确定。在一个家庭里， NC 1中以前未报告的无义突变的分离 COL 10A 1的结构域被证实具有SMCD表型。在第二 家人X型胶原蛋白中的酪氨酸到组氨酸突变已经被 在先证者中确定，但共分离仍有待证明。在 第三个家庭，没有突变尚未确定。 II型胶原蛋白疾病-我们已经确定了4个新的突变， 个体发育不良最严重，所有这些都导致缩短型 II胶原纤维。这些突变都聚集在外显子12之间 和24，进一步增加了不同类型的突变的假设， 和位置导致最大的表型。我们还进一步 临床和分子定义的Stickler综合征家族，表明 第四个Stickler基因的存在，并表明， 严重的视觉表现的并发症可以区分 与COL 2A 1相关的家族以及因其他基因突变而导致的家族。