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Mechanism of disease

Figure 2: Classes of CFTR mutations and their molecular consequences Class I, Production defect; Class II, processing defect; Class III, channel regulation defect; Class IV, conductance defect; Class V, reduced expression.

CFTR protein functions and defects in cystic fibrosis Ion transport

The CFTR protein functions in epithelial cells as a cAMP-regulated anion channel and therefore plays a critical role in transepithelial fluid and electrolyte transport.6

MSDs of CFTR form a

transmembrane, anion-selective pore, which transports mainly Cl-

to a conformation permeable to larger anions, such as bicarbonate (HCO3

glutathione or ATP.7 , but can switch

is also permeant to other anions such as I- Br-, F-

and bioactive substrates such as Anions, which are

allowed to bind in the pore, pass across the membrane according to the

transmembrane electrochemical gradient; therefore, in sweat duct epithelia, CFTR drives re-absorption of Cl-

, whereas in the

intestinal, pancreatic and airway epithelia, CFTR mediates Cl-

and HCO3 - secretion. 8

CFTR also functions as a regulator of other ion transporters in epithelial cells. It has been observed in heterologous systems that functional CFTR inhibits the

-). CFTR ,

ENaC (amiloride-sensitive epithelial sodium channel) activity, leading to reduction of sodium (Na+

) reabsorption

in airway epithelia. It has been therefore hypothesised that mutated CFTR might result in the loss of this regulatory function and cause increased ENaC activity in CF airway epithelia. However, Na+

expression pattern. This has been demonstrated in the pancreatic epithelium (interaction between CFTR and SLC26-A3 and -A6) and possibly in the airways (interaction between CFTR and SLC26-A4 and SLC26-A9). Conversely, CFTR may also be regulated by interaction with other Cl-

absorption is variable in CF organs despite expression of ENaC. Moreover, in the recently implemented porcine CF model, Na+

absorption is not increased in

airway epithelia. As mentioned before, CFTR can also interact via its extreme C-terminal peptide (DTRL) with PDZ- domain-containing proteins, which are important organisers of receptors, ion transporters and regulatory elements present in airway epithelium. For example, reciprocal activation between CFTR and the HCO3

-/Cl- exchangers of

the SLC26 family has been shown. CFTR, therefore, might also regulate HCO3- secretion not only directly by its channel gating but also by interacting with paralogs of the SLC26 family with a tissue-specific

transporters, as demonstrated recently for CFTR and SLC26-A9.8

Transepithelial anion and liquid transport

As CFTR plays a role in transepithelial electrolyte and fluid transport, in a direct and indirect manner, it participates in airway surface liquid (ASL) volume regulation. Healthy and non-inflamed airway surface epithelia display net salt and fluid absorption. In the case of ASL volume depletion, normal airway epithelium switches from net salt absorption to net secretion to rehydrate airway surfaces (Figure 3).9

In CF, Cl-

secretion is strongly limited and ENaC activity is upregulated, resulting in an increased absorption of Na+

and a

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