Cystic fibrosis (CF; OMIM®: 219700) is autosomal recessive, multisystem disease leading to significant morbidity and early death. Characteristic manifestations include recurrent lung infections, malabsorption, malnutrition, and infertility (especially in males). Cystic Fibrosis is caused by thick and sticky mucus due to the disturbances of salt homeostasis in cells. Biochemical hallmark of the disease is elevated sweat chloride concentration.
CF is caused by mutations in the cystic fibrosis conductance regulator gene (CFTR; OMIM®: *602421; HGNC number: 1884), located on chromosome 7. CFTR functions as a chloride channel and controls the regulation of other transport pathways. Asymptomatic carrier parents, who have no physiological or biochemical outcome that enables routine identification, typically have one CFTR mutation; whereas diseased progeny carry at least two mutations, one on each CFTR gene allele. CF has a high incidence in people of Northern European descent, occurring in approximately 1 in 2500 live births.
The most common mutant allele is the F508del mutation , which is a deletion of three basepairs at the 508th codon causing the deletion of a phenylalanine residue and subsequent defective intracellular processing of the CFTR protein that is an important chloride channel. Worldwide, the F508del mutation is responsible for approximately two-thirds (66%) of all CF chromosomes; however, there is great mutational heterogeneity in the remaining one-third of all alleles . The next most frequent mutation was G542TER – a G-to-T change in nucleotide 1756 in exon 11 is responsible for a stop mutation in codon 542 .
Not only is there heterogeneity in the mutations causing Cystic Fibrosis, but the pathogenetic mechanisms also vary. Deletion of phenylalanine-508 appears to cause disease by abrogating normal biosynthetic processing and thereby resulting in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common G551D mutation , appear to be normally processed and, therefore, must cause disease through some other mechanism. G551D mutation, which is within the first nucleotide-binding fold of the CFTR, is the third most common CF mutation, with a worldwide frequency of 3.1% among CF chromosomes . Several mutations result in proteins that are too short because production is ended prematurely. Less common mutations produce proteins that do not use energy normally, do not allow chloride to cross the membrane appropriately, or are degraded at a faster rate than normal. Mutations may also lead to fewer copies of the CFTR protein being produced .
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