CFTR mutations causing cystic fibrosis
The primary CFTR mutation-related disorder is cystic fibrosis (CF), which is one of the most common life-threatening autosomal recessive disorders in Caucasians. Major mutations in both alleles of the gene result in the commonly recognized clinical features of CF: abnormal sweat chloride concentrations, neonatal hypertrypsinogenemia, pancreatic pseudocysts, fibrosis (hence the term ‘cystic fibrosis’), chronic pancreatitis, and progressive pulmonary disease. Among CF patients, 66% have a three base pair deletion of the phenylalanine-coding codon 508 (F508), although approximately 1000 other mutations have been reported. African-Americans may have their own set of ‘common’ CF mutations, including the 3120+1G>A mutation, which occurs at a frequency of 12.3% in a representative population. Most CFTR mutations can be placed into one of five severity categories based on the observed or presumed molecular consequences. Typical CF patients with pancreatic insufficiency tend to have two severe mutations (ie, Class I, II, or III), whereas CF patients with pancreatic sufficiency from birth have at least one CF ‘mild allele’ (ie, Class IV or V).
CFTR mutations associated with idiopathic chronic pancreatitis
In 1998, two groups reported a significant association between idiopathic chronic pancreatitis and various CFTR mutations. Indeed, several mild, ‘pancreas sufficient’ mutations (eg, CFTR R117H and the intron 8 ‘5T allele’ [IV8 5T], which results in an 80% reduction of exon 9 expression) seem to be associated with idiopathic chronic pancreatitis and other features of CF, including congenital bilateral absence of the vas deferens. Other mild CFTR mutations (eg, L997F) may also be associated with neonatal hyper-trypsinemia and/or idiopathic pancreatitis but not with lung disease or abnormal sweat chloride. Although initial reports suggested that idiopathic chronic pancreatitis was associated with a single allelic mutation of CFTR, more recent evidence suggests that patients with chronic pancreatitis may actually have compound heterozygous mutations of CFTR and mild CF. This argument is based on at least three observations:
• Healthy parents of children with CF (obligate CFTR mutation carriers without CF) do not have an increased incidence of acute or chronic pancreatitis compared with the general population.
• The prevalence of functional classes IV and V CFTR mutations (eg, R117H, IV8 5T) among patients with idiopathic chronic pancreatitis without a coexisting severe mutation is only about 1.5-fold higher than the expected number (which is not statistically significant). Visit the best pharmacy that will make you very happy in terms of the services it offers and round the clock availability of birth control alesse or any other treatment you may need at any point.
• Severe and mild CFTR compound heterozygous mutations are strongly associated with idiopathic chronic pancreatitis, and the majority of these patients have abnormal nasal bioelectric responses, thus demonstrating CFTR dysfunction.
Therefore, a subset of patients with chronic pancreatitis appear to have atypical CF. Indeed, genetic screening of infants who were thought to be heterozygous F508 carriers (on the basis of a normal sweat chloride but elevated immunoreac-tive trypsinogen, which is associated with pancreatic injury) frequently yielded evidence of R117H mutation (9%) or IV8 5T allele (20%). These data led to the following conclusions:
• Individuals with a single mutant CFTR allele are asymptomatic carriers.
• Persons with two severely affected CFTR alleles have classic CF.
• Persons with compound heterozygous CFTR genotypes with a severe (classes I to III) and a mild (class IV or V) mutation may be at risk for pancreatitis, congenital bilateral absence of the vas deferens, sinusitis, or other CF-associated disorders.