CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

软骨发育不全的临床和分子研究

• 批准号: 2576520
• 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/2576520
• 关键词: achondroplasia; clinical research; gene expression; gene mutation; genotype; human genetic material tag; human morbidity; human mortality; human subject; infant human (0-1 year); linkage mapping; molecular genetics; preschool child (1-5)

This study has three specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, 2) molecular genetic studies designed to identify correlations between mutations which cause achondroplasia and related disorders and phenotype of affected individuals, and 3) molecular genetic studies designed to identify mutations in other FGFR3 disorders. Clinical studies have continued to collect information on neurologic and respiratory complications of achondroplasia in children less than 4 years of age. To date, a total of 130 cases have been ascertained. Data analysis is ongoing. Molecular genetic studies in our lab have determined that the mutated allele in sporadic cases of achondroplasia is predominantly inherited from the paternal chromosome. Advanced paternal age may play a role in the high mutation rate observed at this site. Studies of DNA from the 10-15% of patients without the typical hypochondroplasia mutation have failed to find additional FGFR3 mutations. These findings support previous speculation that there may be genetic heterogeneity in hypochondroplasia. We have shown, in collaboration with Dr. Max Muenke, that a new craniosynostosis syndrome can result from a specific FGFR3 mutation, also found in isolated craniosynostosis of the coronal sutures and that a newly identified skeletal dysplasia, with profound growth retardation, mental retardation and acanthosis nigricans, also results from a specific FGFR3 mutation. In collaboration with Dr. Jeffrey Baron of NICHD we have identified a possible FGFR3 mutation/polymorphism associated with generalized short stature. Additional studies are underway to clarify these findings.

这项研究具有三个具体目的：1）识别和 刺激性的发病率和死亡率原因的表征 2）分子遗传研究旨在识别 引起疼痛质症和相关疾病和表型的突变 受影响的个体和3）旨在的分子遗传研究 识别其他FGFR3疾病中的突变。 临床研究继续收集有关神经系统和 不到4岁的儿童疼痛的呼吸并发症 年龄。迄今为止，总共确定了130例。数据 分析正在进行中。 我们实验室中的分子遗传研究已经确定突变 偶发性的疼痛病例中的等位基因主要是遗传的 来自父亲染色体。高级父亲时代可能在 在该地点观察到的高突变率。研究DNA的研究 有10-15％的没有典型下软骨突变的患者患有 未能找到其他FGFR3突变。这些发现支持 以前的猜测可能存在遗传异质性 下软骨。 我们已经与Max Muenke博士合作表明了一个新的 颅骨突出综合征可能是由特定的FGFR3突变引起的 在冠状缝合线的孤立颅突变中发现 新确定的骨骼发育不良，较大的生长迟缓， 智力低下和棘皮动物的鼻孔也是由特定的 FGFR3突变。 与NICHD的Jeffrey Baron博士合作，我们已经确定了 可能与广义短相关的FGFR3突变/多态性 身材。正在进行其他研究以阐明这些发现。