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 lipoprot ein[a], is highly polymorphic in human and nonhuman primates. Null all eles, producing no detectable circulating Lp[a] or apo[a] isoforms, ar e found at high frequencies, The molecular basis of null alleles is no t yet known, In baboons, approximately two-thirds of null alleles do n ot produce detectable hepatic transcripts (transcript negative nulls), and one-third of null alleles produce normal amounts of apo[a] transc ripts (transcript positive nulls). We have cloned apo[a] cDNA from a b aboon carrying a transcript positive null allele defective in secretio n from primary hepatocytes. Compared with wild-type cDNA, the null all ele contained an in-frame 47 amino acid deletion in the protease domai n corresponding to one exon of the apo[a] gene. The null allele contai ns an A-->T substitution in the third nucleotide position of the intro n downstream of the deleted exon which alters the donor splice site co nsensus sequence. Thus, this null is likely due to a mutation that pre vents normal mRNA splicing, yielding a shortened protein that may be d efective in intramolecular interactions required for normal processing and secretion of apo[a], This is the first report of a molecular basi s for apo[a] null alleles.