Mutations Affecting Membrane Proteins Cause Diseases

In view of the fact that membranes are located in so many organelles and are involved in so many processes, it is not surprising that mutations affecting their protein constituents should result in many diseases or disorders. Proteins in membranes can be classified as receptors, transporters, ion channels, enzymes, and structural components. Members of all of these classes are often glycosylated, so that mutations affecting this process may alter their function. Examples of diseases or disorders due to abnormalities in membrane proteins are listed in Table 41-5; these mainly reflect mutations in proteins of the plasma membrane, with one affecting lysosomal function (I-cell disease). Over 30 genetic diseases or disorders have been ascribed to mutations affecting various proteins involved in the transport of amino acids, sugars, lipids, urate, anions, cations, water, and vitamins across the plasma membrane. Mutations in genes encoding proteins in other membranes can also have harmful consequences. For example, mutations in genes encoding mitochondrial membrane proteins involved in oxidative phosphorylation can cause neurologic and other problems (eg, Leber's hereditary optic neuropathy; LHON). Membrane proteins can also be affected by conditions other than mutations. Formation of autoantibodies to the acetyl-choline receptor in skeletal muscle causes myasthenia gravis. Ischemia can quickly affect the integrity of various ion channels in membranes. Abnormalities of membrane constituents other than proteins can also be harmful. With regard to lipids, excess of cholesterol (eg, in familial hypercholesterolemia), of lysophospho-lipid (eg, after bites by certain snakes, whose venom contains phospholipases), or of glycosphingolipids (eg, in a sphingolipidosis) can all affect membrane function.

Cystic Fibrosis Is Due to Mutations in the Gene Encoding a Chloride Channel

Cystic fibrosis (CF) is a recessive genetic disorder prevalent among whites in North America and certain parts of northern Europe. It is characterized by chronic bacterial infections of the airways and sinuses, fat maldigestion due to pancreatic exocrine insufficiency, infertility in males due to abnormal development of the vas deferens, and elevated levels of chloride in sweat (> 60 mmol/L).

After a Herculean landmark endeavor, the gene for CF was identified in 1989 on chromosome 7. It was found to encode a protein of 1480 amino acids, named cystic fibrosis transmembrane regulator (CFTR), a cyclic AMP-regulated Cl- channel (see Figure 41-17). An abnormality of membrane Cl- permeability is believed to result in the increased viscosity of many bodily secretions, though the precise mechanisms are still under investigation. The commonest mutation (~70% in certain Caucasian populations) is deletion of three bases, resulting in loss of residue 508, a phenylalanine (AF508). However, more than 900 other mutations have been identified. These mutations affect CFTR in at least four ways: (1) its amount is reduced; (2) depending upon the particular mutation, it may be susceptible to misfolding and retention within the ER or Golgi apparatus; (3) mutations in the nucleotide-binding domains may affect the ability of the Cl- channel to open, an event affected by ATP; (4) the mutations may also reduce the rate of ion flow through a channel, generating less of a Cl- current.

The most serious and life-threatening complication is recurrent pulmonary infections due to overgrowth of various pathogens in the viscous secretions of the respi-

Table 41-5. Some diseases or pathologic states resulting from or attributed to abnormalities of membranes.1

Disease

Abnormality

Achondroplasia (MIM 100800)

Mutations in the gene encoding the fibroblast growth factor receptor 3

Familial hypercholesterolemia (MIM 143890)

Mutations in the gene encoding the LDL receptor

Cystic fibrosis (MIM 219700)

Mutations in the gene encoding the CFTR protein, a Cl- transporter

Congenital long QT syndrome (MIM 192500)

Mutations in genes encoding ion channels in the heart

Wilson disease (MIM 277900)

Mutations in the gene encoding a copper-dependent ATPase

I-cell disease (MIM 252500)

Mutations in the gene encoding GIcNAc phosphotransferase, resulting in absence of the Man 6-P signal for lysosomal localization of certain hydrolases

Hereditary spherocytosis (MIM 182900)

Mutations in the genes encoding spectrin or other structural proteins in the red cell membrane

Metastasis

Abnormalities in the oligosaccharide chains of membrane glycoproteins and glycolipids are thought to be of importance

Paroxysmal nocturnal hemoglobinuria (MIM 311770)

Mutation resulting in deficient attachment of the GPI anchor to certain proteins of the red cell membrane

1The disorders listed are discussed further in other chapters. The table lists examples of mutations affecting receptors, a transporter, an ion channel, an enzyme, and a structural protein. Examples of altered or defective glycosylation of glycoproteins are also presented. Most of the conditions listed affect the plasma membrane.

1The disorders listed are discussed further in other chapters. The table lists examples of mutations affecting receptors, a transporter, an ion channel, an enzyme, and a structural protein. Examples of altered or defective glycosylation of glycoproteins are also presented. Most of the conditions listed affect the plasma membrane.

Carboxyl terminal

Figure 41-17. Diagram of the structure of the CFTR protein (not to scale). The protein contains twelve transmembrane segments (probably helical), two nu-cleotide-binding folds or domains (NBF1 and NBF2), and one regulatory (R) domain. NBF1 and NBF2 probably bind ATP and couple its hydrolysis to transport of Cl-. Phe 508, the major locus of mutations in cystic fibrosis, is located in NBF1.

Carboxyl terminal

Figure 41-17. Diagram of the structure of the CFTR protein (not to scale). The protein contains twelve transmembrane segments (probably helical), two nu-cleotide-binding folds or domains (NBF1 and NBF2), and one regulatory (R) domain. NBF1 and NBF2 probably bind ATP and couple its hydrolysis to transport of Cl-. Phe 508, the major locus of mutations in cystic fibrosis, is located in NBF1.

ratory tract. Poor nutrition as a result of pancreatic insufficiency worsens the situation. The treatment of CF thus requires a comprehensive effort to maintain nutritional status, to prevent and combat pulmonary infections, and to maintain physical and psychologic health. Advances in molecular genetics mean that mutation analysis can be performed for prenatal diagnosis and for carrier testing in families in which one child already has the condition. Efforts are in progress to use gene therapy to restore the activity of CFTR. An aerosolized preparation of human DNase that digests the DNA of microorganisms in the respiratory tract has proved helpful in therapy.

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