The number of kringle IV repeats 3-10 is invariable in the human apo(a) gene

The human apolipoprotein(a) (apo(a)) gene is a member of a family of related genes including plasminogen, apo(a)rg-B and apo(a)rg-C, which are clustered on chromosome 6q 2,7. Apo(a) contains ten different types of plasminogen-like kringle IV repeats (K-IV 1-10) one of which (K-IV 2) varies in number resulting in a remarkable size polymorphism of the protein. Sequence analysis of human apo(a) alleles and indirect evidence have suggested that K-IV 1 and K-IV 3-10 are each present once in individual alleles and that the 3' apo(a) region encompassing kringles IV 3-10, kringle V and the protease domain is invariable. To directly test this, we have constructed a restriction map of the apo(a) gene region from genomic DNA and from a yeast artificial chromosome (YAC) (K-IV 13) which contains the entire apo(a) gene. The presence of a 63 kb ClaI fragment encompassing kringles IV 3-10, kringle V and the protease domain and a 46 kb SwaI fragment, spanning kringles IV 5-10, kringle V and the protease domain was demonstrated by PFGE/Southern blotting in 30 unrelated subjects, who represented a range of apo(a) size alleles containing from 11 to 49 kringles. Our analysis demonstrates that the number of kringles IV 3-10 is invariable in the human apo(a) gene, suggesting that the 3'domain of Apo(a) is functionally important.