Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2

Abstract

A 20-year-old female student underwent renal biopsy because of chance proteinuria and hematuria. Histological study revealed a membranous nephropathy-like appearance by light microscopy. But immunoglobulins and complements were negative in the glomerulus by immunofluorescence study. On the other hand, plasma apolipoprotein E (ApoE) concentration was elevated to more than 2 times the normal range, and the phenotype, genotype, and DNA sequence studies of her ApoE showed homozygous ApoE2/2 and a heterozygous novel missense mutation called ApoE Toyonaka (Ser197Cys). Detailed immunohistochemical studies found that the dense deposits in subepithelial, subendothelial, and mesangial areas contained ApoE. Tandem mass spectrometry also proved a large amount of ApoE in the glomerulus. These findings suggest that ApoE Toyonaka with a homozygous ApoE2/2 may cause a new form of ApoE-related glomerular disease resembling membranous nephropathy.

Apolipoprotein E–related glomerular disorders

“…Immunoglobulin and complement depositions were not specifically obsereved in immunofluorescence studies. Unlike the case reported by Fukunaga et al, 44 foam cells characteristic of apoE2 homozygote glomerulopathy and non-lamellated lipoprotein thrombi as reported by Sakatsume et al 20 were conspicuous in the cases reported by Hirashima et al 45 and Kato et al, 46 respectively. Therefore, in carriers exhibiting both apoE2 homozygote and apoE Toyonaka, the balance of non-immune MN-like lesions and apoE2 homozygote glomerulopathy may be dependent upon the influence of apoE Toyonaka within the hinge region.…”

“…[48][49][50] When apoE Toyonaka is involved in hinge damage, type III HLP induced by defective binding to the LDL receptor in the N-terminal domain of the apoE2 homozygote may be negated due to the dysfunction of the C-terminal domain that connects with lipids. In contrast, altered apoE without lipids may accumulate within the glomerulus and induce EDD in the subepithelial region, as the apoE molecule is relatively small (34 kDa) and rich in arginine, a positively-charged amino acid 4 The other 2 cases exhibiting apoE Toyonaka and apo E2 homozygosity 45,46 were of type III HLP with marked hypertriglyceridemia, which was different from the case presented by Fukunaga et al 44 The serum apoE levels, however, were high in all 3 cases. Spike formations were recognized by light microscopy, and subepithelial and subendothelial EDDs including microbubbles were both observed by electron microscopy.…”

“…21 Membranous nephropathy-like apoE deposition disease (MN-like apoE disease). Recently, a new glomerular disease was identified in non-consanguineous carriers possessing the combination of apoE Toyonaka (Ser197Cys), a novel mutation, and apoE2 homozygote [44][45][46] (Figure 1). The first case reported by Fukunaga et al 44 was a 20-year-old female Japanese patient who underwent renal biopsy because she was found to have chance proteinuria and hematuria.…”

“…Recently, a new glomerular disease was identified in non-consanguineous carriers possessing the combination of apoE Toyonaka (Ser197Cys), a novel mutation, and apoE2 homozygote [44][45][46] (Figure 1). The first case reported by Fukunaga et al 44 was a 20-year-old female Japanese patient who underwent renal biopsy because she was found to have chance proteinuria and hematuria. In silvermethenamine-stained sections of a biopsy specimen, "spike" formations as seen in MN were found in the majority of glomeruli without mesangial proliferation or matrix expansion ( Figure 2b).…”

“…(b) At larger magnification, these electron-dense deposits are shown to consist of microbubbles or microcysts. (c) Immunochemical staining shows apoE-positive deposits, particularly within the subepithelial areas (arrows) 44. Reprinted with permission from Fukunaga M, Nagahama K, Aoki M, et al Membranous nephropathy-like apolipoprotein E deposition disease with apolipoprotein E Toyonaka (Ser197Cys) and a homozygous apolipoprotein E2/2.…”