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Arteriosclerosis, Thrombosis, and Vascular Biology. 1991;11:851-856

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Arteriosclerosis and Thrombosis, Vol 11, 851-856, Copyright © 1991 by American Heart Association


ARTICLES

The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360

H Tenkanen, M Lukka, M Jauhiainen, J Metso, M Baumann, L Peltonen and C Ehnholm
National Public Health Institute, Helsinki, Finland.

Apolipoprotein (apo) A-IV is a protein involved in the metabolism of chylomicrons and high density lipoproteins. This protein displays genetic polymorphism due to two main codominant alleles, A-IV1 and A- IV2. We have identified the mutation that leads to this polymorphism. It is caused by a single-base substitution of guanine for thymine in the third base of codon 360. This substitution leads to a glutamine to histidine change. Direct sequencing of amplified DNA from eight subjects in a three-generation pedigree has demonstrated that the guanine to thymine substitution can explain the apo A-IV polymorphism. In 32 unrelated individuals, a correspondence between apo A-IV phenotype determined by isoelectric focusing and genotype determined with Fnu4HI digestion of amplified DNA could be demonstrated. The enzyme lecithin:cholesteryl acyltransferase (LCAT) is activated by apo A-IV. Under our in vitro conditions, the isoprotein apo A-IV 1-1 is a better LCAT activator than is the isoprotein apo A-IV 2-2. A knowledge of the molecular mechanism underlying the apo A-IV polymorphism will help to elucidate the mechanisms involved in LCAT activation.


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