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Mechanism of disease

CFTR and the cystic fibrosis disease mechanism

Although the relationship between precise mechanisms of CF disease and CFTR dysfunction remains unclear, a better understanding of CFTR mutations now points to novel therapies, which can ultimately make a difference in the clinical setting and provide considerable hope for the future

Iwona M Pranke Isabelle Sermet-Gaudelus INSERM U845, Pediatric Lung Disease Unit, Pediatric CF Center, Necker Hospital, Paris Descartes University, France

Cystic fibrosis (CF) is an autosomal recessive disease, caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.1

It affects

one in 2500–4500 newborns among Caucasians. The main clinical characteristics of CF are pancreatic insufficiency and progressive lung disease due to chronic airway obstruction because of hyperviscous and dehydrated infected mucus, the leading cause of morbidity and mortality. While the most well characterised defect is an abnormal transepithelial chloride (Cl-

) transport,

the absence or the dysfunction of CFTR in cells impacts many other cellular processes. Recent findings have helped to better understand the complex biogenesis and function of the wild type protein and the consequences of CFTR loss of function.

CFTR protein structure and biogenesis


The cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7) is a cAMP-regulated chloride channel that belongs, as a peculiar member, to the ATP-binding cassette (ABC) transporter superfamily. CFTR is expressed principally in the apical membrane of epithelial cells. This multidomain glycoprotein of 1480 amino acids and a molecular weight of ~170 kDa is composed of five domains in two Figure 1: Schematic representation of CFTR protein structure

MSD 1, membrane spanning domain 1; MSD 2, membrane spanning domain 2; NBD 1, nucleotide binding domain 1; NBD 2, nucleotide binding domain 2; R, regulatory domain; P, phosphorylation.

symmetrical halves (Figure 1), each comprising a membrane-spanning domain (MSD1/MSD2), and a cytoplasmic nucleotide-binding domain (NBD1/NBD2). These two halves are connected by the fifth, regulatory domain (R), which is a unique feature of CFTR among other ABC transporters.1,2 helical segments of MSD1 and MSD2,


linked by intermediate extracellular loops and four intracytoplasmic loops (CLs 1 to 4), assemble to form the transmembrane channel, while the NBDs have the capacity to bind and hydrolyse ATP. Together with the NBDs, the R domain regulates the channel gating.1,2

The R

domain contains serine residues that are phosphorylated by the cAMP-dependent

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