A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports

Abstract

Background: Lipoprotein glomerulopathy is a rare and newly recognized glomerular disease that can lead to kidney failure. Its pathological features include the presence of lipoprotein embolus in the loop cavity of glomerular capillaries. It is believed that apolipoprotein E gene mutation is the initiator of the disease. Since the discovery of lipoprotein glomerulopathy, 16 different apolipoprotein E mutations have been reported worldwide, but most of these cases are sporadic. Here we report two cases of lipoprotein glomerulopathy, a Chinese son and his father, with a novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys).

Case presentation: Case 1, a 33-year-old Chinese man, was hospitalized on 3 March 2014 owing to edema and weakness of facial and lower limbs for 1 month. Laboratory data showed urine protein 3+, hematuria 2+, serum creatinine 203 μmol/L, uric acid 670 μmol/L, total cholesterol 12.91 mmol/L, triglyceride 5.61 mmol/L, high-density lipoprotein 1.3 mmol/L, low-density lipoprotein 7.24 mmol/L, apolipoprotein B 2.48 g/L, and lipid protein (a) 571 mg/L. Renal tissue examined by immunofluorescence and electron microscopy indicated lipoprotein glomerulopathy. Case 2, 55-year-old father of case 1, was hospitalized on 12 January 2016 owing to edema of his lower extremities for 6 months. Laboratory data showed urine protein 2+, hematuria 2+, serum creatinine 95 μmol/L, uric acid 440 μmol/L, total cholesterol 4.97 mmol/L, triglyceride 1.91 mmol/L, high-density lipoprotein 1.18 mmol/L, low-density lipoprotein 3.12 mmol/L, apolipoprotein B 2.48 g/L, and lipid protein (a) 196 mg/L. Renal tissue examined by immunofluorescence and electron microscopy indicated lipoprotein glomerulopathy. Apolipoprotein E mutation test showed that they had the same gene mutation, a novel type of apolipoprotein E mutation. Based on their clinical presentation and examination findings, they were diagnosed with lipoprotein glomerulopathy. Case 1 was treated with prednisone and dual plasma replacement, followed by simvastatin, nifedipine, triptolide, and angiotensin II receptor blocker drug therapy. After 1 month, the edema symptoms of the patient were alleviated, and urinary protein, serum creatinine, and uric acid were quantitatively reduced. Case 2 was treated with Tripterygium wilfordii and angiotensin II receptor blocker drugs for 3 weeks, and his edema symptoms were alleviated, and urinary protein, serum creatinine, and uric acid were quantitatively reduced.

Conclusions: The apolipoprotein E mutation in the two cases we reported was a familial aggregation phenomenon, and the mutation is a novel type, which we named ApoE Ganzhou (Arg43Cys). The location of the gene mutation is close to the most common mutation type of lipoprotein glomerulopathy, ApoE Kyoto (Arg25Cys), so we speculate that its pathogenic role might be the similar to that of ApoE Kyoto (Arg25Cys).

Keywords: ApoE Ganzhou; Apolipoprotein E; Case report; Lipoprotein glomerulopathy.

Fig. 1.

Histological analysis for the renal biopsy specimens in case 1 under light microscope. A Hardened glomerulus [hematoxylin and eosin (HE) staining, ×200]. B Glomerular periballoon fibrosis [periodic acid–Schiff–methenamine (PASM) staining, ×200]. C Dilation of capillary loops and presence of thrombotic substances in the lumen [periodic acid–Schiff (PAS) staining, ×200]. D Polyhemoglobin deposition in the glomeruli (Masson staining, ×200). E Electron microscopy results showing capillary endothelial cells with obvious vacuolar degeneration and a large number of lipid vacuolar protein substances in the cavity (scale bar, 5 μm)

Fig. 2

DNA sequence analysis for ApoE mutation. ApoE gene was sequenced in genomic DNA from both patients (A, case 1; B, case 2) and a family member (C, mother of case 1). Both patients had a heterozygous ApoE mutation of C-to-T transition in exon 3 that changed the amino acid at position 43 of the mature protein from arginine to cysteine. Cys, cysteine; Arg, arginine

Fig. 3

Pedigree of the family. The proband (II-1, case 1) in this case report is indicated by the arrow. The square and the circle represent male and female, respectively. Blank and black symbols respectively represent unaffected family members and patients for ApoE Ganzhou (Arg43Cys). The gene mutation of the proband came from his father, I-1, case 2 in this report. Cys, cysteine; Arg, arginine

Fig. 4.

Histological analysis of the renal biopsy specimens in case 2. A Hardened glomerulus under light microscope (PASM staining, ×200). B Glomerulus with segmental sclerosis under light microscope (PASM staining, ×200). C Immunofluorescence microscopy results showing positive ApoE. D and E Electron microscopy results showing capillary endothelial cells with obvious vacuolar degeneration, and a large number of lipid vacuolar protein substances in the cavity (scale bar, 2 μm for D and 0.5 μm for E)

Fig. 5

Structure and mutations of ApoE. A Important regions of ApoE and the difference among E2, E3, and E4 at positions 112 and 158. B Seventeen different ApoE mutations reported, and a novel mutation, ApoE Ganzhou (Arg43Cys), marked in red. LRBS LDL-receptor binding site, HR hinge region, LBP lipid binding position, Cys cysteine, Arg arginine, Glu glutamic acid, Lys lysine, Pro proline, Gly glycine, Leu leucine, Ser serine, del deletion, Ala alanine, Gln glutamine, Asp aspartic acid, Tyr tyrosine