Abstract 5484: Mutations in Scavenger Receptor-BI/II Result in a Novel Dyslipidemia, with Increased HDL and Lipoprotein(a)
Backgound: Scavenger receptor class B, Type 1(SR-B1/II) is a multiple ligand lipoprotein receptor. It mediates uptake of cholesteryl esters from lipoproteins and promotes the removal of excess cellular cholesterol. Mice deficient in SR-B1 have elevated plasma levels of HDL and LDL and increased atherosclerotic lesions. No known human mutations leading to decreased SR-B1 activity have been described. Lipoprotein (a) (Lp(a)), a LDL-like lipoprotein, has not been previously investigated as a possible ligand for SR-B1/II.
Methods and Results: Nine unrelated subjects, who had high plasma HDL (>80 mg/dl) and high Lp(a) (>100 mg/dl), with normal level LDL lipoproteins, were identified from 1036 individuals enrolled in the Johns Hopkins Family Heart Study. All were healthy adult siblings of a proband with premature coronary heart disease. The SR-B1/II gene was sequenced in these subjects, including all 13 exons and their junctions, as well as the proximal promoter. All subjects were found to be either heterozygous for an SR-B1/II mutation or had a common polymorphism. Three different nucleotide transitions in coding regions of SR-BI/II were found in five subjects. These resulted in a non-conservative amino acid change that either altered receptor function, as assessed by site directed mutagenesis studies, or decreased protein translation. Two mutations were in intron/exon junctions. One was a 2 base pair transition that flanked an exon splice site, while the other was a T to G transversion in a polypyrimidine site, resulting in exon skipping and a 32 amino acid in frame deletion. None of these mutations were found in 190 control subjects. The remaining two patients in the study had a common polymorphism (Exon 8 C1050T) that does not lead to an amino acid change but is previously known to decrease mRNA levels of SR-BI and increase HDL. To confirm that SR-BI can bind Lp(a), we showed that a HeLa cell line stably transfected with human SR-B1 bound approximately 10-fold more Lp(a), as assessed by flow cytometry, compared to untransfected control cells. In summary, we show that Lp(a) is a ligand for SR-BI and that mutations of SR-BI can lead to a novel lipoprotein phenotype, namely elevated HDL associated with increased levels of Lp(a).