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.

本研究有两个具体的目的：1）识别和 软骨发育不全发病和死亡原因的特征， 和（2）分子遗传学研究，旨在确定基因， 软骨发育不全和特征突变引起的条件，和 突变和疾病之间可能存在的相关性 迄今为止的临床研究主要集中在五岁以下的儿童身上 年龄。 以前的研究表明，这个年龄组的人有一个 大大增加了死亡的风险。 在我们的回顾性研究中 在约翰霍普金斯大学和德克萨斯大学进行随访的患者中， 休斯顿，我们发现软骨发育不全儿童的死亡率为7% 在不到五岁的年龄组。 我们随后招募了100名 孩子们，在他们进入研究的时候都不到五岁， 软骨发育不全的神经和呼吸系统并发症 所有 参加研究的儿童已经进行了头部和颈部的CT或MRI， 多导睡眠图、超声心动图和心电图，以及 神经科、发育科、骨科和肺部会诊。 数据 对100名儿童的初步评估仍在进行分析。 我们实验室和其他实验室的分子遗传学研究表明， 软骨发育不全基因与4p末端标记的关系。 随后，Wasperson等人表明，FGFR 3基因突变 （成纤维细胞生长因子3）导致软骨发育不全;他们的研究在16 患者提示突变的高度同质性。 我们有 分析了154名软骨发育不全的无关患者的DNA， 证实了这些观察结果：其中150人在24小时内发生了G到A的突变。 核苷酸1138，而3在相同位置处具有G到C的颠换。 对该核苷酸突变频率的计算表明， 是人类基因组中已知的最易突变的核苷酸。