title: The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360.
abstract: 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.
authors.affiliation: National Public Health Institute, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Tenkanen
authors.forename: M
authors.initials: M
authors.lastname: Lukka
authors.forename: M
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: J
authors.initials: J
authors.lastname: Metso
authors.forename: M
authors.initials: M
authors.lastname: Baumann
authors.forename: L
authors.initials: L
authors.lastname: Peltonen
authors.forename: C
authors.initials: C
authors.lastname: Ehnholm
mesh_terms: D000595:Amino Acid Sequence; D001054:Apolipoproteins A / Q000235:genetics* / Q000494:pharmacology; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000187:drug effects; D005838:Genotype; D005973:Glutamine / Q000235:genetics*; D006150:Guanine Nucleotides / Q000235:genetics; D006639:Histidine / Q000235:genetics*; D006801:Humans; D007525:Isoelectric Focusing; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D013942:Thymine Nucleotides / Q000235:genetics
chemical_list: D001054:Apolipoproteins A; D006150:Guanine Nucleotides; D013942:Thymine Nucleotides; C022205:apolipoprotein A-IV; D005973:Glutamine; D006639:Histidine; D007862:Phosphatidylcholine-Sterol O-Acyltransferase