Membranes mutations affecting, diseases caused

MUTATIONS AFFECTING MEMBRANE PROTEINS CAUSE DISEASES... 

The metabolism ofHDL is complex because of the multiple mechanisms by which HDL particles are synthesized and modified plasma. Many factors, including genetic variation, can alter HDL levels and affect CHD risk. ApoA-I is the major HDL apoprotein, and its plasma concentration is a more powerful inverse predictor of CHD risk than is the HDL-C level. Mutations in the apoA-I gene that cause HDL deficiency are variable in their clinical expression and often are associated with accelerated atherogenesis. The membrane transporter ABCAl facilitates the transfer of free cholesterol from cells to HDL. When ABCAl is defective, the acquisition of cholesterol by HDL is greatly diminished, and HDL levels are markedly reduced. Loss-of-function mutations of ABCAl cause Tangier disease, a genetic disorder characterized by extremely low levels ofHDL and cholesterol accumulation in the liver, spleen, tonsils, and peripheral nerves. 

Peroxisomal Diseases. Peroxisomal diseases are caused by mutations affecting either the synthesis of functional peroxisomal enzymes or their incorporation into peroxisomes. For example, adrenoleukodystrophy probably involves a mutation that decreases the content of a transporter in the peroxisomal membrane. Zellweger s syndrome is caused by the failure to complete the synthesis of peroxisomes. 

Mutations that affect the structure of membrane proteins (teceptots, ttanspotters, ion channels, enzymes, and stmctutal proteins) may cause diseases examples include cystic fibrosis and familial hypetcholes-terolemia. 

Defects of nuclear DNA also cause mitochondrial diseases. As mentioned above, the vast majority of mitochondrial proteins are encoded by nDNA, synthesized in the cytoplasm and imported into the mitochondria through a complex series of steps. Diseases can be due to mutations in genes encoding respiratory chain subunits, ancillary proteins controlling the proper assembly of the respiratory chain complexes, proteins controlling the importation machinery, or proteins controlling the lipid composition of the inner membrane. All these disorders will be transmitted by mendelian inheritance. From a biochemical point of view, all areas of mitochondrial metabolism can be affected (see below). 

Free radicals seek to combine with electrons from stable compounds and thus produce more free radicals in the process. The cell membrane is one of the most vulnerable structures to free radical damage. Also affected are low-density lipoproteins, other proteins, and DNA. Free radicals alter functions of these molecules or cause mutations in DNA. There are mechanisms in place to repair free radical damage, but the repair is not completely effective and becomes less so with age. The result is heart disease, cancer, arthritis, cataracts, and aged skin (Elson, 2009). 

---