APOE – Lipoprotein Glomerulopathy

Apolipoprotein E (APOE; HGNC:613) is a key mediator of lipid transport and receptor-mediated clearance of remnant lipoproteins. Lipoprotein glomerulopathy (LPG; MONDO:0012725) is a rare autosomal dominant glomerulopathy characterized by dilated glomerular capillary lumina filled with lipoprotein thrombi, resulting in proteinuria, nephrotic syndrome, and progressive renal dysfunction.

Genetically, LPG is associated with heterozygous APOE variants showing incomplete penetrance. Over 25 unrelated probands have been reported with pathogenic APOE alleles, including three with the Arg145Pro (Sendai) variant (PMID:9176854), and the c.127C>T (p.Arg43Cys) (Kyoto) mutation detected in multiple families (PMID:10432380). Segregation analysis has confirmed one additional mother–daughter pair with concordant LPG and the same mutation, supporting dominant transmission.

The APOE variant spectrum in LPG comprises predominantly missense substitutions altering receptor‐binding residues (e.g., c.127C>T (p.Arg43Cys), c.518T>C (p.Leu173Pro)) and small in‐frame deletions (e.g., c.485_493del (p.Leu162_Lys164del)). A founder effect for the Sendai variant has been demonstrated in Japanese LPG cohorts (PMID:23407349).

Functional studies reveal that mutant apoE proteins have markedly reduced LDL receptor binding and altered proteoglycan interactions. Recombinant p.Arg43Cys (Kyoto) displaces LDL at only 10% efficiency of wild-type (PMID:10432380), while the Sendai variant exhibits enhanced endothelial proteoglycan binding, promoting glomerular lipid deposition (PMID:10428296). Viral transduction of apoE Sendai into apoE-deficient mice reproduces LPG pathology in vivo (PMID:16431249).

Not all APOE variants lead to LPG; for instance, the Q187E (Toranomon) allele is associated with type III hyperlipoproteinemia without glomerular lipoprotein thrombi in a diabetic nephrosclerosis case (PMID:11877595), underscoring additional genetic or environmental modifiers.

Integration of genetic and experimental data supports a pathogenic mechanism whereby altered apoE–lipoprotein interactions provoke intraglomerular lipoprotein aggregation. APOE sequencing should be incorporated into the diagnostic workup of patients presenting with unexplained proteinuria and type III dyslipidemia. Early identification enables tailored therapy—lipid-lowering agents, LDL apheresis, or newer lipid modulators—and may improve renal outcomes.

Key Take-Home: APOE genotyping is clinically useful for definitive diagnosis of LPG and guides targeted lipid-modifying treatments.

References

• Journal of the American Society of Nephrology • 1997 • Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. PMID:9176854
• Kidney international • 1999 • A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. PMID:10432380
• Nephron. Clinical practice • 1999 • Lipoprotein glomerulopathy: significance of lipoprotein and ultrastructural features. PMID:10412734
• American journal of kidney diseases • 2002 • A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. PMID:11877595
• American journal of kidney diseases • 2006 • Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. PMID:16431249
• Journal of human genetics • 2013 • A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. PMID:23407349

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