Epidemiologic data of recent years have identified an important role of HDL deficiency in the etiology of
atherosclerosis. Biochemical data suggest that some of these deficiencies may be a consequence of defects in the structural genes of HDL
apolipoproteins or of plasma
enzymes that modify HDL. We analyzed the genetic defect in a 42-yr-old patient suffering from
corneal opacities and complete absence of
HDL cholesterol but not of
coronary artery disease, thus clinically resembling
fish eye disease. The observation of an abnormal immunoblot banding pattern of
apolipoprotein A-I (
apo A-I) and of reduced
lecithin: cholesterol acyltransferase (LCAT) activity in plasma led to sequence analysis of the genes for
apo A-I and LCAT in this patient and his family. Direct sequencing of polymerase chain reaction amplified
DNA segments containing the exons of the candidate genes, resulted in the identification of a frameshift mutation in
apo A-I while the LCAT sequence was identical to the wild type. The
apo A-I mutation was predictive for an extensive alteration of the COOH-terminal sequence of the encoded
protein. Evidence for the release of this
mutant protein into the plasma compartment and for the absence of normal
apo A-I was derived from ultraviolet
laser desorption/ionization mass spectrometry analysis. Our results suggest that a defective
apo A-I is the causative defect in this case of HDL deficiency with
corneal opacities.