http://www.ygyh.org/cf/cause.htmClick 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)

The Gene for Cystic Fibrosis

CFTR stands for Cystic Fibrosis Transmembrane

Conductance Regulator. (Cystic Fibrosis because that is the

disorder it causes when it doesn’t work properly; Transmembrane

because it sits in the cellmembrane and spans across it;and Conductance Regulator

because it is one of the proteinsthat control how ions move in and

out of cells). CFTR is also thename for the gene that carries the code to make the CFTR protein.

The 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.

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.

Over 1,000 mutations in CFTR have been found.

ΔF508 accounts for 70% of CF-causing

mutations.

6

Diagram explaining the change in CFTR to create the ∆(Deletion of) F508 mutation.

CF Mutations can be classified by the effect they have on the CFTR protein.

8

9

I

Defective

Production

II

Defective

Processing

III

Defective

Regulation

IV

Defective

Conductance

V

Reduced

Amounts

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.

Class I CFTR Mutations

I

Defective

Production

Class 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.

II

Defective

Processing

Class 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.

III

Defective

Regulation

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.

Class IV CFTR Mutations

IV

Defective

Conductance

Class V CFTR Mutations

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. V

Reduced

Amounts