CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

软骨发育不全的临床和分子研究

• 批准号: 5203396
• 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/5203396
• 关键词: achondroplasia; computed axial tomography; echocardiography; electrocardiography; gene expression; gene frequency; gene mutation; human genetic material tag; human morbidity; human mortality; human subject; infant human (0-1 year); linkage mapping; magnetic resonance imaging; medical complication; molecular genetics; nervous system disorder; preschool child (1-5); respiratory disorder

This study has two specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, and (2) molecular genetic studies designed to identify the gene for achondroplasia and characterize mutations causing the condition, and possible correlations between mutation and disease. Clinical studies to date have focused on children less than five years of age. Previous work has shown that persons in this age group have a substantially increased risk of mortality. In our retrospective study of patients followed at Johns Hopkins and the University of Texas at Houston, we found a 7% mortality rate among children with achondroplasia in the less than five year age group. We have subsequently enrolled 100 children, all less than five at the time they entered the study, to look at neurologic and respiratory complications of achondroplasia. All children entered in the study have had CT or MRI of the head and neck, polysomnography, echocardiography and electrocardiography, and neurologic, developmental, orthopedic and pulmonary consultations. Data analysis is still in progress on the initial evaluations of 100 children. Molecular genetic studies in our lab and others have demonstrated linkage of the achondroplasia gene to markers on the distal tip of 4p. Subsequently, Wasmuth et al showed that mutations in the FGFR3 gene (fibroblast growth factor 3) cause achondroplasia; their studies in 16 patients suggested a high degree of homogeneity of mutations. We have analyzed DNA from 154 unrelated patients with achondroplasia and have confirmed these observations: 150 of them had a G to A mutation at nucleotide 1138, while 3 had a G to C transversion at the same position. Calculations of mutation frequency at this nucleotide suggest that it is the single most highly mutable necleotide known in the human genome.

这项研究有两个具体的目的：1）识别和 刺激性的发病率和死亡率原因的表征 （2）旨在识别基因的分子遗传研究 刺激性和表征导致病情的突变，并且 突变与疾病之间的可能相关性。 迄今为止的临床研究集中在不到五年的儿童上 年龄。 以前的工作表明，这个年龄段的人有一个 大幅增加了死亡率的风险。 在我们的回顾性研究中 在约翰·霍普金斯（Johns Hopkins）和德克萨斯大学（University of Dexas） 休斯顿，我们发现疼痛性儿童的死亡率为7％ 在不到五岁的小组中。 我们随后招收100 儿童进入研究时不到五个，看 在疼痛质症的神经系统和呼吸并发症上。 全部 参加研究的孩子的头部和颈部有CT或MRI， 多摄影学，超声心动图和心电图学，以及 神经系统，发育，骨科和肺部咨询。 数据 对100名儿童的初始评估仍在进行分析。 我们实验室和其他人的分子遗传研究已经证明了联系 在4p的远端尖端上的肌浮肿基因的基因。 随后，Wasmuth等人表明FGFR3基因中的突变 （成纤维细胞生长因子3）引起疼痛质症；他们的研究在16 患者建议突变的高度同质性。 我们有 分析了154例无关腺泡患者的DNA，患有 确认了这些观察结果：其中150个在 核苷酸1138，而3在同一位置具有G到C横向。 该核苷酸的突变频率的计算表明它是 人类基因组中已知的最高度可突变的坏死球。