The effects of altered apolipoprotein A-I structure on plasima HDL concentration

Approximately 46 human apolipoprotein A-I (apoA-I) coding sequence mutations have been reported to date. Roughly half of these Mutations are associated with lower than average plasma concentrations of high-density lipoprotein (HDL) apoA-I. Mutations associated with low HDL apoA-I concentrations fall into two main categories: those which poorly activate the enzyme lecithin:cholesterol acyltransferase (LCAT) and those associated with amyloidosis. These phenotypically distinct groups of mutations are uniquely localized in different regions of the apoprotein sequence. Mutations associated with abnormal LCAT activation are located within repeats 5, 6, and 7, corresponding to amino acids 121 to 186, while many of the mutations found in amyloid deposits are clustered at the amino terminus of the protein, namely residues I to 90. These observations strongly support the idea that the tertiary structure of apoA-I determines its intravascular fate and ultimately the steady state concentration of plasma HDL. (C) 2002, Elsevier Science Inc.