title: Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians.
abstract: High plasma concentrations of lipoprotein(a) [Lp(a)], a covalent low-density lipoprotein-apolipoprotein(a) [apo(a)] complex, are associated with coronary heart disease and stroke. Heritability of Lp(a) levels is high and the major locus determining Lp(a) concentrations is the apo(a) gene. We here demonstrate that a G-->A substitution at the +1 donor splice site of the apo(a) kringle (K) IV type 8 intron occurs with a high frequency ( approximately 6%) in Caucasians but not in Africans and is associated with congenital deficiency of Lp(a) in plasma. This mutation alone accounts for a quarter of all 'null' apo(a) alleles in Caucasians. RT-PCR analysis based on apo(a) illegitimate transcription in lympho- blastoid cells demonstrated that the donor splice site mutation results in an alternative splicing of the K IV type 8 intron and encodes a truncated form of apo(a). Expression of the alternatively spliced cDNA analogue in HepG2 cells showed that the truncated apo(a) form is secreted but is unable to form the covalent Lp(a) complex. Immunoprecipitated plasma apo(a) from homozygotes for the mutation was almost completely fragmented. Taken together, our data indicate that a failure in complex formation followed by fast degradation in plasma of the truncated free apo(a) is one mechanism which underlies the null Lp(a) type associated with the donor splice site mutation.
authors.affiliation: Institute of Medical Biology and Human Genetics, University of Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Ogorelkova
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: G
authors.initials: G
authors.lastname: Utermann
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001054:Apolipoproteins A / Q000235:genetics*; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D003001:Cloning, Molecular; D005006:Ethnicity / Q000235:genetics; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D007438:Introns / Q000235:genetics; D018082:Kringles / Q000235:genetics; D017270:Lipoprotein(a) / Q000172:deficiency / Q000235:genetics*; D008113:Liver Neoplasms / Q000473:pathology; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D019655:Quantitative Trait, Heritable; D012326:RNA Splicing; D014162:Transfection; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics
chemical_list: D001054:Apolipoproteins A; D017270:Lipoprotein(a); D046911:Macromolecular Substances