Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency with premature coronary atherosclerosis, tuboeruptive and planar xanthomas

Raul D. Santos, Ernst J. Schaefer, Bela D. Asztalos, Eliana Polisecki, Jian Wang, Robert A. Hegele, Lilton R. C. Martinez, Marcio H. Miname, Carlos E. Rochitte, Protasio L. Da Luz, and Raul C. Maranhao

Lipid Clinic, Heart Institute- InCor University of Sao Paulo Medical School Hospital, Sao Paulo, SP 05403-9000

Corresponding Author: raul.santos{at}incor.usp.br

Our aim was to characterize high density lipoprotein (HDL) subspecies and fat soluble vitamin levels in a kindred with familial apolipoprotein (apo) A-I deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apo A-1, tubo-eruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two dimensional gel electrophoresis revealed undetectable apo A-I, decreased amounts of small a-3 migrating apo A-II particles, and only modestly decreased normal amounts of slow a migrating apo A-IV and apo E-containing HDL, while in the 8 heterozygotes there was loss of large a-1 HDL particles. There were no significant decreases in plasma fat soluble vitamin levels noted in either homozygotes or heterozygotes, as compared to normal control subjects. Our data indicate that isolated apo A-I deficiency results in marked HDL deficiency with very low apoA-II a-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apo E HDL particles, tubo-eruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

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