Cystic Fibrosis Transmembrane Conductance Regulator

• OMIM: 602421
• UniProt: P13569
• MGI: 88388

The Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR) is a stuck on the surface of cells protein, known as a chloride channel, which occurs mainly in the cell membrane of epithelial cells of fish and terrestrial vertebrates. Mutations in the CFTR gene in humans lead to the absence or limited function of the channel, which cause of CF ( cystic fibrosis) and congenital aplasia of the vas deferens ( CAVD ) is.

Biosynthesis

The CFTR gene is located on chromosome 7 in the q31.2 region. It is 250 kb long and consists of 27 exons. Transcribed mRNA has a length of 6123 bases and, after translation, and post-translational modification occurs, the CFTR protein with 1480 amino acids.

Protein structure

The protein is an integral protein, which belongs to the cAMP regulated ion channels. It has two subunits, each with six transmembrane domains that constitute the primary transport channel. In addition, the protein has two nucleotide - binding domains (NBD 1 and 2) and a cytoplasmic ( located within the cell) regulatory domain (R). Said R domain can be phosphorylated by the protein kinase A and thereby activated. CFTR contains other binding domains of protein -protein interactions, thereby to regulate, inter alia, the transport of the bicarbonate and other channels. It is also a member of the ATP-binding ABC transporter.

Function and pathology

The CFTR protein regulates the water and salt transport in the plasma membrane and epithelial cells.

CFTR mutations limit the chloride ion transport from the cell or bring it to a halt. Consequently, there is a difference in concentration, as many ions in the cell, but only a few are in the secretion. Due to the present in the cell osmotic forces the secretion of water is removed. The secretion is thick, can be broken down and clogged by bad example, fine channels in the lungs or the vas deferens.

Mutation classes

We distinguish six classes of mutation:

Classes 1 to 3 are severe mutations, while 4-6 are among the slight mutations - here the function of the channel is not completely inhibited.

Whether the mutation leads to CF or CAVD, depends on the severity of the mutations from both alleles.

Known mutations

F508

In this mutation, the amino acid phenylalanine is absent due to a deletion of three nucleotides at the point 508. The protein can not be folded because it does not pass into the endoplasmic reticulum, thus it belongs to the class -2 mutations.

R117H

If a milder but still frequently occurring mutation, it belongs to the class 4 mutations, which is often found in CBAVD patients. It is a missense mutation in the amino acid arginine has been replaced by histidine at the 117th position. This mutation leads to a lower chloride ion conductivity.

Polymorphisms

In addition to the mutations and polymorphisms are commonly found in CAVD and in CF patients. Polymorphisms belonging to the class 5 mutations. It has been found that there are differences in the Thymidinanzahl at the end of the 3 ' splice site before exon 9 One distinguishes between T5, T7 and T9. The less thymidine is present, the more decreases the splicing of exon 9 As a result, the CFTR proteins are not correctly folded and thus reduced. Here we also speak of partial penetrance, ie penetrating power. The partial penetrance can be explained by a genetic factor, the (TG ) m- polymorphism. Because the efficiency of splicing of exon 9 depends inter alia on the TG repeats. The more TG repeats in intron 8 are available, the less efficient is the splicing.