2The Gene for Cystic Fibrosis Click on this link for a demonstration of CFTR and its function.A triumph of molecular genetics in 1989—a research team headed by Francis Collins, who was then an HHMI investigator at the University of Michigan, and Lap-Chee Tsui and John Riordan of Toronto's Hospital for Sick Children discovered an errant gene that is responsible for Cystic Fibrosis (CF). The researchers also identified the specific mutation, a missing snippet of genetic material, involved in most cases of CF.(Howard Hughes Medical Institute)CFTR
3CFTR CFTR stands for Cystic Fibrosis Transmembrane Conductance Regulator. (CysticFibrosis because that is thedisorder it causes when it doesn’twork properly; Transmembranebecause it sits in the cellmembrane and spans across it;and Conductance Regulatorbecause it is one of the proteinsthat control how ions move in andout of cells). CFTR is also thename for the gene that carries thecode to make the CFTR protein.CFTR
4The CFTR protein is located in the cell membrane of certain cells called epithelial cells. These cells can join together to create a sheet of cells that line the inside and outside of many organs including lungs, sinuses, pancreas and skin. CFTR is an ion channel. It allows ions (charged particles, like chloride) to move across the epithelial cell membrane to enter or leave the cell.CFTR
5CF is an inherited disorder CF is an inherited disorder. A child inherits CF when he or she receives one copy of a non-working CFTR gene from each parent. This is called recessive inheritance. If a person has one working copy of CFTR and one copy that does not work, he or she is called a carrier. Carriers of CF are healthy, but they may pass non-working CFTR to their children.CFTR
6CFTR Over 1,000 mutations in CFTR have been found. ΔF508 accounts for 70% of CF-causing mutations.
7CFTRDiagram explaining the change in CFTR to create the ∆(Deletion of) F508 mutation.
85 Classes of CFTR Mutations CF Mutations can be classified by the effect they have on the CFTR protein.
95 Classes of CFTR Mutations DefectiveProductionIIDefectiveProcessingIIIDefectiveRegulationIVDefectiveConductanceVReducedAmounts
10Class I CFTR Mutations I Defective Production Class I mutations are so disruptive that the CFTR message is never translated into a protein. These mutations usually insert a stop signal too early in the DNA, which prevents protein production.IDefectiveProduction
11Class II CFTR Mutations Class II mutations cause the protein not to fold into its normal shape. These proteins never make it to the cell membrane. The most common Class II mutation is ΔF508, or a deletion of the amino acid phenylalanine (F) at amino acid position 508 in the protein.IIDefectiveProcessing
12Class III CFTR Mutations Class III mutations result in a protein that is made and transported to the cell membrane, but once it is there it does not work properly and cannot move ions across the membrane. Sometimes coding for one incorrect amino acid in the whole protein is enough to create a defective protein.IIIDefectiveRegulation
13Class IV CFTR Mutations Class IV mutations result in a protein that is successfully made and transported to the cell membrane. However, once the protein is in the membrane it does not function at normal levels.IVDefectiveConductance
14Class V CFTR Mutations V Reduced Amounts Class V mutations result in lower production of a normal CFTR protein. The protein works properly, but there is not enough of it made to meet the needs of the cell.VReducedAmounts