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.