CYSTIC FIBROSIS GENE MODIFIER STUDY

囊性纤维化是一种复杂的多系统疾病，具有常染色体隐性遗传特征。囊性纤维化基因已被克隆并鉴定。该基因编码氯离子通道。该基因的突变导致这种重要蛋白质的产生显著减少，缺乏这种蛋白质会导致气道、胰管和其他器官的分泌物异常，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的特定突变（基因型）来预测。相比之下，囊性纤维化所造成的肺损伤，即占该疾病发病率和死亡率大部分的损伤，是非常不同的，即使在具有相同突变的个体中也是如此。即使是兄弟姐妹在疾病的表达上也会有显著的差异。这导致了一种假设，即一定有其他基因，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，其中杂交实验已经在小鼠染色体区域上发现了至少一个与人类19号染色体长臂相对应的遗传修饰位点。马歇尔博士和他在多伦多大学的同事们正在收集囊性纤维化谱系（先证、兄弟姐妹、父母和其他人），努力绘制19号染色体修饰位点的精细图谱。这项研究已经证明，19号染色体上的一个位点会影响新生儿肠囊性纤维化并发症的严重程度，这种情况被称为胎粪肠梗阻。

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.