C/T polymorphism in the 5' untranslated region of the apolipoprotein(a) gene introduces an upstream ATG and reduces in vitro translation.
Elevated plasma levels of lipoprotein(a) [Lp(a)] are a significant-independent risk factor for arteriosclerosis. Interindividual levels of Lp(a) vary nearly 1000-fold and are mainly due to inheritance that is linked to the locus of the apolipoprotein(a) [apo(a)] gene. A search was made for sequence variants in the 5' flanking region of the apo(a) gene that affect its expression. A C to T transition at position +93 from the transcription start site was found with a frequency of 14% in the study population. In transient transfection assays in HepG2 cells, luciferase reporter gene constructs with a T at this position were associated with a 58% reduction in luciferase activity compared with the more common allele. This single base variant had no significant effect on the binding of nuclear regulatory proteins; however, it introduced an additional upstream ATG initiation codon with its own in-frame stop codon. Furthermore, equivalent levels of mRNA were produced in HepG2 cells transfected with reporter gene constructs containing either a T or a C at position +93. In vitro translation experiments using transcripts derived from either variant apo(a) promoter revealed a 60% reduction in translation associated with the T allele. Hence, the additional ATG created by the T at position +93 in the 5' flanking region of the apo(a) gene impairs the efficiency of translation from the bona fide ATG initiation codon.
Zysow
B R
BR
Falk Cardiovascular Research Center, Stanford University Medical School, CA 94305-5246, USA.
Lindahl
G E
GE
Wade
D P
DP
Knight
B L
BL
Lawn
R M
RM
D001053:Apolipoproteins / Q000097:blood / Q000235:genetics*; D053241:Apoprotein(a); D001483:Base Sequence; D002460:Cell Line; D018014:Gene Transfer Techniques; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics*; D017270:Lipoprotein(a); D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis
D001053:Apolipoproteins; D017270:Lipoprotein(a); D053241:Apoprotein(a)