Cystic Fibrosis Flashcards
Channelopathy
Ion channel dysfunction
How many ion channel genes have been associated with human disease?
~60
Most common diseases associated with ion channel dysfunction - Ach receptors
Congenital myasthenia
Frontal lobe epilepsy
Most common diseases associated with ion channel dysfunction - Voltage-gated Na+
Epilepsy with febrile seizures
Myotonia/periodic paralysis
Long QT syndrome
Most common disease associated with ion channel dysfunction - Voltage-gated K+
Long QT syndrome
Most common disease associated with ion channel dysfunction - ATP-sensitive K+ channel
Neonatal diabetes
Most common disease associated with ion channel dysfunction - Voltage-gated Ca2+
Migraine
Cystic fibrosis
Incurable hereditary disease affecting lungs and endocrine glands
Most important pathological abnormalities occur in the lungs where the accumulation of mucus leads to cycles of chronic infection/inflammation and progressive destruction of alveolar tissue
What causes cystic fibrosis?
Defective gene that encodes a 1500 aa protein: cystic fibrosis transmembrane conductance receptor (CFTR)
CFTR structure
2 transmembrane domains
2 cytoplasmic nucleotide binding domains
Regulatory region (R domain)
Normal CFTR
Chloride channel
ATP-gated -> requires binding of ATp to both NBDs to open AND requires phosphorylation of serine residues on regulatory R domain to open
Closes when CFTR hydrolyses bound ATP to ADP
Phosphorylation is required for opening but not closing
*** reduced Cl- movement
CF-associated mutations of CFTR
Over 70% of CF cases can be attributed to a single mutation – deletion of Phe 508 in NBD1. The mutant protein folds incorrectly and is degraded within the cell without reaching the membrane.
Class I mutation in CFTR
Defective protein synthesis
Class II mutation in CFTR
Defective processing
Class III mutation in CFTR
Defective regulation
Class IV mutation in CFTR
Defective conduction
Management therapies from cystic fibrosis
Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus (physiotherapy)
Administering nutritional therapy (cystic fibrosis can cause the pancreas to become blocked with mucus, reducing secretion of digestive enzymes – poor digestion/absorption of nutrients)
Managing complications
