Apolipoprotein(a) is the Product of a Pseudogene: Implications for the Pathophysiology of Lipoprotein(a)

Abstract

Apolipoprotein(a) [apo(a)] is an apolipoprotein unique to lipoprotein(a) [Lp(a)]. Although it has no known function, Lp(a) is a risk factor for accelerated atherothrombosis. We hypothesize that LPA, the gene which encodes apo(a), is a heretofore unrecognized unprocessed pseudogene created by duplication of PLG, the gene which encodes plasminogen. Unprocessed pseudogenes are genes which were created by duplication of functional genes and subsequently lost function after acquiring various mutations. This hypothesis explains many of the unusual features of Lp(a) and apo(a). Also, this hypothesis has implications for the therapy of elevated Lp(a) and atherothrombosis theory. Because apo(a) is functionless, the diseases associated with elevated levels of Lp(a) are due to its impact on blood viscosity.

Keywords: apolipoprotein(a); atherothrombosis; blood viscosity; lipoprotein a; pseudogene.

Figure 1. Generation of an unprocessed pseudogene by unequal recombination of homologous genes due to misalignment

In LPA, the gene which encodes apolipoprotein(a), two Alu elements, the most common type of SINE (short interspersed nuclear element), are present in the untranslated 5’ region. (Modified from original artwork by Dennis Pietras. From Wikimedia Commons.)

Figure 2. Chromosome 6q25.3-6q26

The genes LPAL2 (lipoprotein(a)-like 2), an unprocessed pseudogene, LPA, and PLG, the gene encoding plasminogen, are clustered in this region. Pseudogenes are present on both sides of LPA (large arrows). A long intergenic noncoding RNA (lincRNA) is indicated by the small arrow. (Courtesy of Ensembl 92. http://uswest.ensembl.org/Homo_sapiens/Location/Overview?db=core;g=ENSG00000198670;r=6:160237877-160957878)