Biology of Disease

protein is one of a group of transporters called ATP-binding cassette (ABC)

proteins. These are multidomain structures: all have two cytosolic ATP-bind-

ing domains or cassettes and two transmembrane domains each consisting

of several helices. However, the most studied of the ABC transporters is the

transmembrane conductance regulator protein, which regulates a chloride

channel. Unlike Tangier disease, which is extremely rare, defects with this

transporter lead to the much more common condition, cystic fibrosis.

Cystic Fibrosis

Cystic fibrosis (CF) is a multisystem, inherited disorder characterized by the

secretion of very viscous mucus secretions in the lungs, digestive tract and

associated organs, and epididymis. This results in chronic respiratory disease,

malabsorption, cirrhosis and electrolyte disturbances. The clinical features of

CF are shown in Table 16.1.

Feature Consequences

Recurrent respiratory infections irreversible lung disease

Pancreatic insufficiency malabsorption; poor growth; steatorrhea (excessive fat in feces)

Intestinal obstruction in neonates

(meconium ileus)

failure to thrive

Diabetes mellitus (late onset) failure to control blood sugar levels

Epididymal epithelial malfunction male sterility

Table 16.1Clinical features of cystic fibrosis

Cystic fibrosis is the commonest fatal, homozygous recessive disorder of the

Caucasian population affecting about one in 2000 people in the UK, with

one in 20 Caucasians carrying one copy of the mutated gene. The prevalence

of CF varies throughout the world with certain populations reporting higher

incidences. The onset may be at birth or later in childhood. Cystic fibrosis

is characterized by decreased permeability of the apical membrane of epi-

thelial tissues lining the lungs and other organs to chloride ions (Cl–) that

results from mutations (Chapter 15) in the CFTR gene that encodes the cystic

fibrosis transmembrane conductance regulator (Figure 16.3). This protein is a

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

W^dad\nd[Y^hZVhZ

Figure 16.3 Schematic of the cystic fibrosis

transmembrane conductance regulator protein

(CFTR). Redrawn from Akabas, MH (2000) Cystic

fibrosis transmembrane conductance regulator.J.

Biol. Chem.275:3729–3732.

X]VeiZg&+/ MEMBRANE, ORGANELLE AND CYTOSKELETAL DISORDERS

)*) W^dad\nd[Y^hZVhZ

COO-

+NH 3

Plasma

membrane

Transmembrane

helix

ATP binding

domain