title: An initiation codon mutation in the apoC-II gene (apoC-II Paris) of a patient with a deficiency of apolipoprotein C-II.
abstract: We have identified the genetic defect that leads to a deficiency of apoC-II in the proband from the Paris kindred. Analysis of the apoC-IIParis DNA by Southern blot hybridization revealed no major gene rearrangements, but sequencing of polymerase chain reaction-amplified apoC-IIParis DNA revealed an A to G transition that changed the initiation AUG (methionine) codon to GUG (valine). Potential initiation of translation at the closest inframe methionine codon eliminates the entire signal peptide and the first 8 amino-terminal residues of apoC-II which would prevent apoC-II secretion into plasma. In agreement with this, no apoC-II was detected in the patient's plasma by radioimmunoassay or by two-dimensional gel electrophoresis and immunoblotting. Direct sequencing of amplified patient DNA from 12 different polymerase chain reaction samples demonstrated the presence of the A to G substitution in all, indicating that the proband is a homozygote for the defect. We propose that in the apoC-IIParis gene, a mutation in the initiation methionine codon prevents the normal initiation of apolipoprotein synthesis and leads to a deficiency of apoC-II. This initiation methionine mutation represents a new type of molecular defect that can result in Type I hyperlipoproteinemia.
authors.affiliation: Molecular Disease Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
authors.forename: S S
authors.initials: SS
authors.lastname: Fojo
authors.forename: J L
authors.initials: JL
authors.lastname: de Gennes
authors.forename: J
authors.initials: J
authors.lastname: Chapman
authors.forename: C
authors.initials: C
authors.lastname: Parrott
authors.forename: P
authors.initials: P
authors.lastname: Lohse
authors.forename: S S
authors.initials: SS
authors.lastname: Kwan
authors.forename: J
authors.initials: J
authors.lastname: Truffert
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
mesh_terms: D000328:Adult; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence; D015139:Blotting, Southern; D003062:Codon / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005796:Genes; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009693:Nucleic Acid Hybridization; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*; D012016:Reference Values; D015183:Restriction Mapping
chemical_list: D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D003062:Codon; D012333:RNA, Messenger; D004247:DNA