Cystic Fibrosis Mutations: Class II

Class II  Mutations:

An example of a Cystic Fibrosis class II mutation is Delta F508

This class contains a defective CFTR protein processing and trafficking. The post translational processing and transport reduce the number of CFTR proteins that are delivered to the cell surface.The protein is unable to fold correctly.

Lung function range in patients with Delta F508:

This chart was created with data from CFTR2.org and CFF.org

Cystic Fibrosis Mutations: Class I

Class I Mutations:

An example of a Cystic Fibrosis nonsense-stop mutation is G542X.

This class includes premature termination codons (PTCs)- a point mutation in the DNA sequence that results in a premature stop. Missing information is the cause of the premature stop and as a result, the protein product is usually nonfunctional and incomplete. The missing genetic information stops cells from making complete CFTR proteins.

Lung function range in patients with G542X:

This chart was created with data from CFTR2.org and CFF.org

Normal CFTR protein channels

Normal Cystic Fibrosis Transmembrane Conductance Regulators (CFTR) transport chloride and bicarbonate ions through the cell membrane of epithelial cells. This helps to regulate fluid and electrolyte balance in the epithelial tissues throughout the body. Epithelial tissue is found in the lungs, sinuses, pancreas, intestines, reproductive system, and sweat glands. When ion flow fails, the ionic concentration of the secretions is modified. The epithelia no longer maintains surface hydration and can cause the duct lumens to obstruct. 

CFTR activity is determined by the quantity of CFTR channels at the cell surface, the amount of time each channel is open (gating), and the amount of ions conducted in a given time in each channel (conductance). CFTR quantity is determined by gene transcription, proper splicing, and mRNA translation, processing and trafficking and the maturation of the CFTR protein and the delivery of it to the cell's surface, and surface stability- the amount of time a CFTR channel is at the surface before being removed and recycled.

According to in vitro experimentation (Bompadre SG, Sohma Y, Li M, Hwang TC. G551D and G1349D), CFTR protein channels have an open probability of ~40%, meaning they are open approximately 40% of the time.

Cystic Fibrosis Mutations

The genetic mutation that causes Cystic Fibrosis was discovered in 1989. Mutations on a single gene- the Cystic Fibrosis Transmembrane Regulator (hereafter referred to as CFTR) causes the most common, fatal genetic disease.

Since the discovery of the CFTR gene, researchers have identified over 1,800 mutations. These mutations are grouped into different classes and types dependent upon how the mutation affects the key protein produced by the CF gene.

The CFTR gene is located on the 7th chromosome and is composed of 250,000 DNA nucleotides. In healthy people (those with normally functioning CFTR genes), the CFTR is located on the surface of the cells that line the lungs and other organs. The protein made by the CFTR is a chloride channel. Chloride flows in and out of the cells through a "doorway" and water flows behind in. The water keeps the mucus this and moves it out as well.

What is a nucleotide?
A structural components of DNA and RNA. A nucleotide consists of one of the following chemicals: adenine, thymine, guanine, or cytosine, plus a molecule of sugar and one of phosphoric acid.

What does the CFTR gene do?
The CFTR protein functions as a channel for the movement of chloride ions in and out of our cells. This is important for the salt and water balance on epithelial surfaces (the tissue that lines the cavities and surfaces throughout the body). A balanced level is highly important for the lungs and pancreas, however, due to mutations of the CFTR, these organs are negatively affected. The mutations affect the composition of the mucus layer (airway surface liquid, ASL- a liquid and mucus gel layer that contains salt) that lines the epithelial surfaces in the lungs and pancreas. A disruption in of ion transport affects the salt concentration in the sweat. This is why sweat tests are used as a diagnostic measure.

Although a diagnosis of Cystic Fibrosis is usually straightforward, genetic testing is preferred. Genotype is not the final arbiter of a clinical diagnosis of CF. Diagnosis is primarily based on: sweat testing, nasal potential difference, and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF.

In order to Cystic Fibrosis, a person must have inherited two defective genes from both parents. The mutations can be the same (homogenous) or different (heterogenous). For example, a person could have the 621+1g>t mutation and the F508del mutation. The heterogeneity of CFTR mutations in various populations makes mutation detection rates extremely challenging. A small number of CF patients have only one or no CFTR mutations identified.

Why do mutations matter?
Not every case of Cystic Fibrosis is the same. A CF Patient's mutation determines what happens on a cellular level.

Identification of the underlying mechanisms that cause CF allows for researchers to better understand how certain medications can help specific CF patients. CFTR targeted therapies could treat the issues on a cellular level, which would address the cause of CF as opposed to the symptoms of CF.