CYSTIC FIBROSIS GENE MODIFIER STUDY

囊性纤维化基因修饰研究

• 批准号: 6304900
• 负责人: BRUCE C MARSHALL
• 金额: $ 0.16万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6304900
• 关键词: clinical research; cystic fibrosis; family genetics; genetic markers; human genetic material tag; human subject; intestine obstruction; linkage mapping

Cystic fibrosis is a complex multi-system disease which is inherited as an autosomal recessive trait. The cystic fibrosis gene has been cloned and characterized. The gene encodes a chloride ion channel. Mutations in the gene lead to markedly diminished production of this important protein, and deficiency results in abnormal secretions in airways, pancreatic ducts, and other organs, resulting in the clinical syndrome of cystic fibrosis. The effects of mutations on the pancreas can be predicted by knowing the specific mutation (the genotype) in the cystic fibrosis gene. In contrast, the lung damage which occurs in cystic fibrosis, damage which represents the majority of the morbidity and mortality of the disease, is quite variable, even in individuals with the same mutation. Even siblings can have striking discrepancies in the expression of the disease. This has led to the hypothesis that there must be other genes, designated modifier genes, that influence the clinical severity of cystic fibrosis. This hypothesis is supported by experimental data in the cystic fibrosis gene knockout mouse, where cross-breeding experiments have identified at least one genetic modifier locus on a mouse chromosomal area corresponding to the long arm of human chromosome 19. Dr. Marshall and his colleagues at the University of Toronto are collecting cystic fibrosis pedigrees (probands, siblings, parents, and others) in an effort to fine-map the chromosome 19 modifier locus. The study has already demonstrated that a locus on chromosome 19 influences the severity of a bowel complication of cystic fibrosis, a condition called meconium ileus in the newborn.

囊性纤维化是一种复杂的多系统疾病，常染色体隐性遗传。囊性纤维化基因已被克隆和鉴定。该基因编码一个氯离子通道。该基因的突变会导致这种重要蛋白质的产生显著减少，缺陷会导致呼吸道、胰管和其他器官的异常分泌，从而导致囊性纤维化的临床综合征。突变对胰腺的影响可以通过了解囊性纤维化基因中的特定突变(基因型)来预测。相比之下，囊性纤维化中发生的肺损伤是相当不同的，即使在具有相同突变的个体中也是如此。囊性纤维化是这种疾病的发病率和死亡率的主要组成部分。即使是兄弟姐妹，在疾病的表现上也可能有惊人的差异。这导致了一种假设，即一定有其他基因，即指定的修饰基因，影响囊性纤维化的临床严重程度。这一假设得到了囊性纤维化基因敲除小鼠的实验数据的支持，在那里，杂交实验已经在小鼠染色体区域确定了至少一个与人类19号染色体长臂相对应的遗传修饰基因。多伦多大学的马歇尔博士和他的同事们正在收集囊性纤维化家系(先证者、兄弟姐妹、父母和其他人)，以努力精细地绘制19号染色体修饰基因的位置图。这项研究已经证明，19号染色体上的一个基因座影响囊性纤维化的肠道并发症的严重程度，这种情况在新生儿中被称为胎粪性肠梗阻。