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.
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