囊肿性纤维化

Mutation of CFTR
Genetics of CF
• Epithelial dysfunction
– Epithelia containing CFTR protein exhibit array of normal functions
• Volume absorbing (airway, distal intestine) • Salt absorbing without volume (sweat ducts) • Volume secretory (proximal intestine, pancreas)
• Most common life limiting recessive trait among whites
Cystic Fibrosis
• Prognosis improving
– >38% of CF patients are older than 18 – 13% of CF patients are older than 30
Pathophysiology
• Lung
– Raised trans-epithelial electric potential difference – Absence of cAMP-dependent kinase and PKC-regulated chloride transport – Raised sodium transport and decreased chloride transport – Alternative calcium-regulated chloride channel in airway epithelia which is a potential therapeutic target
• Median survival
– Males: 32 years – Females: 29 years
Genetics of CF
• Autosomal recessive • Gene located on chromosome 7 • Prevalence- varies with ethnic origin
Genetics of CF
• Most common mutation
– Occurs in 70% of CF chromosomes – 3 base pair deletion leading to absence of phenylalanine at position 508 (DF508) of the CF transmembrane conductance regulator (CFTR)
– Dysfunction in CFTR gene leads to different effects on patterns of electroHale Waihona Puke Baiduyte and water transport
Persistence of CF
• Is there a reason why CF mutations are so prevalent? • Hypothetical resistance to morbidity and mortality associated with cholera • Evidence shows intestinal epithelial cells homozygous for the DF508 mutation are unresponsive to the secretory effects of cholera toxin
Cystic Fibrosis
Paolo Aquino Internal Medicine-Pediatrics January 13, 2005
Outline
• • • • • What is cystic fibrosis (CF)? What causes CF? What are the manifestations? How do you diagnose CF? How do you treat CF?
– 1 in 3000 live births in Caucasians in North America and Northern Europe – 1 in 17,000 live births of African Americans – 1 in 90,000 live births in Hawaiian Asians
Genetics of CF
• DF508 mutation leads to improper processing and intracellular degradation of the CFTR protein
• Other mutations in the CF gene produce fully processed CFTR proteins that are either non-functional or partially functional
• Large number (>1000) of relatively uncommon muations (~2%)
Genetics of CF
• Difficult to use DNA diagnosis to screen for heterozygotes • No simple physiologic measurements yet available for heterozygote detection
Genetics of CF
• The CFTR protein
– Single polypeptide chain, 1480 amino acids – Cyclic AMP regulated chloride channel – Regulator of other ion channels – Found in the plasma membrane of normal epithelial cells
Cystic Fibrosis
• Inherited monogenic disorder presenting as a multisystem disease. • Typically presents in childhood
– 7% of CF patients diagnosed as adults