Patient-Oriented and Epidemiological Research
Nonsynonymous SNPs in LPA homologous to plasminogen deficiency mutants represent novel null apo(a) alleles[S]

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Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.

apolipoprotein (a)
endoplasmic reticulum
Golgi
kringle structure
null allele
protein modeling

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This work was supported by funding from the Maurice Wilkins Centre, the Dunedin School of Medicine Deans Bequest fund, and a Marjorie McCallum Award to B.M.M. The authors declare that they have no conflicts of interest with the contents of this article

Abbreviations:

    GWAS

    genome-wide association study

    KIV

    kringle IV

    KV

    kringle V

    Lp(a)

    lipoprotein (a)

    PDB

    Protein Data Bank

    TGOLN2

    trans-Golgi network 2

[S]

The online version of this article (available at https://www.jlr.org) contains a supplement.