pediatrics
Cystic Fibrosis
Etiology of Cystic Fibrosis
Cystic fibrosis is carried as an Autosomal Recessive by about 3% of the White population. The responsible gene has been localized on the long arm of chromosome 7. It encodes a membrane-associated protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The most common gene variant, F508del, occurs in about 85% of CF alleles; CFTR is a cyclicadenosinemonophosphate (cAMP)–regulated chloride channel, regulating chloride, sodium, and bicarbonate transport across epithelial membranes. A number of additional functions are considered likely. Disease manifests only in people who are homozygous. People who are heterozygous may show subtle abnormalities of epithelial electrolyte transport but are clinically unaffected. TheCFTRvariants have been divided into 6 classes based on how the variant affects the function or processing of the CFTR protein. Patients with class I, II, or III variants are considered to have a more severe genotype that results in little or no CFTR function, whereas patients with 1 or 2 class IV, V, or VI variants are considered to have a milder genotype that results in residual CFTR function. However, there is no strict relationship between specific variants and disease manifestation, so clinical testing (ie, of organ function) rather than genotyping is a better guide to prognosis.CFTRvariants can involve frameshift (a deletion or insertion in a DNA sequence that shifts the way a sequence is read) or nonsense (stop) mutations. 