Human Molecular Genetics, Vol 8, 2087-2096, Copyright © 1999 by Oxford University Press
M Ogorelkova, A Gruber and G Utermann
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.
ARTICLES
Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians
Institute of Medical Biology and Human Genetics, University of Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria.
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