Molecular basis of an apolipoprotein[a] null allele: a splice site mutation is associated with deletion of a single exon.
Apolipoprotein[a] (apo[a]), a unique component of atherogenic lipoprotein[a], is highly polymorphic in human and nonhuman primates. Null alleles, producing no detectable circulating Lp[a] or apo[a] isoforms, are found at high frequencies. The molecular basis of null alleles is not yet known. In baboons, approximately two-thirds of null alleles do not produce detectable hepatic transcripts (transcript negative nulls), and one-third of null alleles produce normal amounts of apo[a] transcripts (transcript positive nulls). We have cloned apo[a] cDNA from a baboon carrying a transcript positive null allele defective in secretion from primary hepatocytes. Compared with wild-type cDNA, the null allele contained an in-frame 47 amino acid deletion in the protease domain corresponding to one exon of the apo[a] gene. The null allele contains an A-->T substitution in the third nucleotide position of the intron downstream of the deleted exon which alters the donor splice site consensus sequence. Thus, this null is likely due to a mutation that prevents normal mRNA splicing, yielding a shortened protein that may be defective in intramolecular interactions required for normal processing and secretion of apo[a]. This is the first report of a molecular basis for apo[a] null alleles.
Cox
L A
LA
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245, USA.
Jett
C
C
Hixson
J E
JE
D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D053241:Apoprotein(a); D001483:Base Sequence; D019976:Cloning, Organism; D017931:DNA Primers; D005091:Exons; D006801:Humans; D007438:Introns; D017270:Lipoprotein(a); D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D010215:Papio; D010958:Plasminogen / Q000737:chemistry / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
D001053:Apolipoproteins; D017931:DNA Primers; D017270:Lipoprotein(a); D012333:RNA, Messenger; D010958:Plasminogen; D053241:Apoprotein(a)