Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomenulopathy

Variants of apolipoprotein E (apoE) have been linked to lipoprotein glomeru lopathy, a new glomerular disease characterized by the deposition of lipopr oteins in mesangial capillaries. One third of affected patients are heteroz ygous for apoE2 Sendai (Arg(145)->Pro). Variants of apoE can also produce t ype III hyperlipoproteinemia (HLP). Recessive type III HLP is caused by apo E2 (Arg(158)->Cys), a mutant with diminished low-density lipoprotein (LDL) receptor binding but half-normal heparin binding. Dominant type III HLP is caused by mutations that markedly alter heparin binding but modestly reduce receptor binding. This study examined whether apoE2 Sendai (Arg(145)->Pro) was functionally different from type In HLP-producing apoE variants by exp ressing apoE3, apoE2 (Arg(158)->Cys), apoE1 (Arg(146)->Glu), a dominant apo E variant, and apoE2 Sendai (Arg(145)->Pro) in the baculovirus system. LDL receptor binding was studied using recombinant apoE complexed to phospholip id vesicles and to very low-density lipoprotein from a patient with familia r apoE deficiency. Compared with apoE3, receptor-binding activities of apoE 2 (Arg(158)->Cys), apoE1 (Arg(146)->Glu), and apoE2 Sendal (Arg(145)->Pro) all were less than 5%. Heparin-binding activities were 53%, 23%, and 66%, r espectively, of apoE3. The distribution of apoE2 Sendai among the major pla sma lipoprotein fractions was similar to that of apoE3 and apoE2 (Arg(158)- >Cys). ApoE2 Sendai (Arg(145)->Pro) represents the only known mutation with in the heparin-binding domain of apoE (residues 142 through 147), revealing diminished receptor binding and almost normal heparin binding. These uniqu e characteristics of apoE2 Sendai (Arg(145)->Pro) may relate to the develop ment of lipoprotein glomerulopathy.