Molecular Genetics Of Human Skeletal Dysplasias

人类骨骼发育不良的分子遗传学

• 批准号: 6530331
• 负责人: Clair A. Francomano
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/6530331
• 关键词: Mennonite; achondroplasia; adolescence (12-20); child (0-11); chondrodystrophy; congenital skeletal disorder; disease /disorder etiology; disease /disorder model; functional /structural genomics; gene expression; genetically modified animals; human subject; laboratory mouse; model design /development; molecular genetics; patient oriented research; proteomics

Work on this project has focused on an autosomal recessive form of skeletal dysplasia, Cartilage Hair Hypoplasia (CHH) and the achondroplasia family of skeletal dysplasias. Cartilage hair hypoplasia has recently been found to be caused by mutations in the RNMP gene, which encodes an RNA that participates in the mitochondrial Ribonuclear Protein complex. Mutational analysis in Amish patients with CHH and non-Amish CHH patients is ongoing. The achondroplasia family of skeletal dysplasias includes three previously recognized diagnoses and one that has been defined under this project. The three well-established conditions are achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Work published by our lab in the past described a new syndrome, Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN). All four disorders in this family of conditions are caused by mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Work over the past two years has focused on the creation and characterization of two mouse models for FGFR3 disorders. Using a knock-in strategy, mice heterozygous for K644E and K644M mutations have been generated. Ongoing work is focused on creation of mice with K644N mutations, to model the human disorder hypochondroplasia. We are anticipating functional genomic and proteomic analysis of the nervous system and skeleton of these mice, in order to better understand the pathogenesis of these three disorders. Clinical efforts include examination of the causes of morbidity and mortality in achondroplasia, and description of previously uncharacterized skeletal dysplasias.

该项目的工作集中在骨骼发育不良，软骨发育不全（CHH）和骨骼发育不良的疼痛家族的常染色体隐性形式上。最近发现软骨发育不足是由RNMP基因突变引起的，RNMP基因编码参与线粒体核糖核蛋白复合物的RNA。 CHH和非Amish CHH患者的Amish患者的突变分析正在进行中。 骨骼发育不良的肌肉症家族包括三个先前认可的诊断，并且在该项目下定义了一个。这三个良好的疾病是腺质，下降体性发育不全（TD）。我们的实验室在过去发表的工作描述了一种新综合征，严重的因子质和发育延迟和棘皮动物nigricans（Saddan）。该条件系列中的所有四种疾病都是由编码成纤维细胞生长因子受体3（FGFR3）的基因中的突变引起的。过去两年中的工作集中在FGFR3疾病的两个鼠标模型的创建和表征上。使用敲门策略，已经产生了用于K644E和K644M突变的小鼠。持续的工作集中在创建具有K644N突变的小鼠，以建模人类疾病下降体质。我们正在预期这些小鼠的神经系统和骨骼的功能基因组和蛋白质组学分析，以便更好地了解这三种疾病的发病机理。 临床努力包括检查肌浮肿的发病率和死亡率的原因，以及以前未表征的骨骼发育不良的描述。