Epidemiologic and genetic data suggest an inverse relationship between plasma
high density lipoprotein (
HDL) cholesterol and the incidence of premature
coronary artery disease. Some of the defects leading to low levels of HDL may be a consequence of mutations in the genes coding for HDL
apolipoproteins A-I and A-II or for
enzymes that modify these particles. A proband with plasma
apoA-I and
HDL cholesterol that are below 15% of normal levels and with marked bilateral
arcus senilis was shown to be heterozygous for a 45-base pair deletion in exon four of the
apoA-I gene. This most likely represents a de novo mutation since neither parent carries the mutant allele. The
protein product of this allele is predicted to be missing 15 (Glu146-Arg160) of the 22
amino acids comprising the third amphipathic helical domain. The HDL of the proband and his family were studied. Using anti-A-I and anti-A-II
immunosorbents we found three populations of HDL particles in the proband. One contained both
apoA-I and A-II, Lp(A-I w A-II); one contained
apoA-I but no A-II, Lp(A-I w/o A-II); and the third (an unusual one) contained
apoA-II but no A-I. Only Lp(A-I w A-II) and (A-I w/o A-II) were present in the plasma of the proband's parents and brother. Analysis of the HDL particles of the proband by
sodium dodecyl sulfate-
polyacrylamide gel electrophoresis revealed two
protein bands with a molecular mass differing by 6% in the vicinity of 28 kDa whereas the HDL particles of the family members exhibited only a single
apoA-I band. The largely dominant effect of this mutant allele (designated
apoA-ISeattle) on HDL levels suggests that HDL particles containing any number of mutant
apoA-I polypeptides are catabolized rapidly.