A Novel Apolipoprotein E Mutation (p.Arg150Cys) in a Chinese Patient with Lipoprotein Glomerulopathy
Lipoprotein glomerulopathy (LPG) is a rare inherited renal disorder characterized by the presence of lipoprotein thrombi in the dilated glomerular capillary lumina, elevated plasma levels of apolipoprotein E (apoE), and proteinuria. The disease predominantly affects individuals of Japanese and Chinese descent, with approximately 117 cases reported to date. Although several studies have implicated mutations in the APOE gene as a potential cause of LPG, conflicting evidence suggests that not all individuals with APOE variants develop the disease. This study presents a novel APOE mutation, p.Arg150Cys, identified in a Chinese family with one LPG patient and an asymptomatic carrier, providing further insights into the role of APOE mutations in LPG pathogenesis.
The study was conducted in compliance with the Declaration of Helsinki and approved by the Ethics Committee of Shenzhen University. Written informed consent was obtained from all participants. The proband was a 21-year-old Chinese woman who was in good health until December 2016, when moderate proteinuria was detected during a routine antenatal examination. Throughout her pregnancy, she experienced moderate to severe proteinuria, with levels reaching up to 5.2 g/day. Four months after delivering a healthy baby girl, she was admitted to the hospital for further evaluation. The patient had no known family history of renal disease or lipidosis.
Upon admission, the patient’s height was 162 cm, and her weight was 55 kg. Her blood pressure was 115/77 mmHg, and she did not exhibit pedal edema. Laboratory tests revealed significant proteinuria (4.0 g/day), a glomerular filtration rate of 145 mL/min, and the presence of blood cells in the urine sediment (5–8 red blood cells per high-power field). Twenty-four-hour urine protein excretion was measured at 2.4 g. Other laboratory findings included a white blood cell count of 5.08 × 10^9/L, hemoglobin of 119 g/L, platelet count of 146 × 10^9/L, albumin of 38 g/L, blood urea nitrogen of 4.2 mmol/L, serum creatinine of 45.8 mmol/L, uric acid of 525.6 mmol/L, total cholesterol (TC) of 8.53 mmol/L, low-density lipoprotein cholesterol (LDL-C) of 6.44 mmol/L, high-density lipoprotein cholesterol of 1.34 mmol/L, triglycerides (TG) of 1.56 mmol/L, and fasting blood glucose of 4.46 mmol/L. Tests for hepatitis B surface antigen, anti-hepatitis C antibody, and antinuclear antibody were negative, and complement levels were within the normal range. An abdominal ultrasound revealed normal renal size and shape but marked splenomegaly.
A percutaneous renal biopsy was performed to establish a definitive diagnosis. Light microscopy examination of 21 glomeruli revealed two with global sclerosis. The glomerular volume was slightly increased, with markedly dilated capillaries containing pale-staining thrombi in a layered structure. Mesangial cells and stroma exhibited mild to moderate proliferation, and some glomeruli had small synechiae between the capillaries and Bowman capsules. Oil red O staining demonstrated numerous lipid droplets in the glomerular capillary lumina, but foam cells were absent in both the glomeruli and tubulointerstitium. Interstitial edema, focal inflammatory cellular infiltration, mild interstitial fibrosis, and tubular atrophy were also observed. Fluorescent microscopy showed trace to 1+ linear deposits of immunoglobulin M, but other immunoglobulins, C3, C4, and C1q were not detected. Strong, segmental staining for apoE and apoB was observed in the capillary lumina. Electron microscopy examination of one glomerulus revealed that almost all dilated capillary lumina were occluded by numerous lipid granules and lamellate vacuoles.
Genetic analysis was conducted to investigate the role of APOE mutations in the patient’s condition. Exon 4 of the APOE gene was analyzed in four individuals using DNA sequencing. Genomic DNA was extracted from blood samples using the DNA Blood Magen Kit, and PCR amplification was performed using specific primers for exon 4. The PCR products were sequenced using an ABI automated DNA sequencer. The sequences of two control individuals matched the reference APOE sequence, while the patient and her mother exhibited a c.308C>T substitution in exon 4, resulting in a missense mutation (p.Arg150Cys). This novel variant was named APOE Shenzhen. The patient’s mother, who was heterozygous for the mutation, did not show any clinical symptoms or signs of renal damage.
The patient’s laboratory characteristics revealed significantly elevated levels of plasma TG, TC, LDL-C, and apoE compared to non-carriers of the APOE mutation. In contrast, her mother’s plasma lipid and lipoprotein levels were within the normal range. To manage the patient’s condition, she was treated with fenofibrate and perindopril. After two months of treatment, her total cholesterol decreased to 5.1 mmol/L, triglycerides to 1.33 mmol/L, and 24-hour urinary protein output to 2.03 g. Her renal function remained normal during this period.
The findings of this study highlight the potential role of APOE mutations in the pathogenesis of LPG. The novel APOE Shenzhen variant (p.Arg150Cys) was identified in two family members, but only the daughter presented with LPG, suggesting that additional factors may contribute to disease development. Previous studies have shown that mutations in the APOE gene can impair the binding of apoE to the LDL receptor, leading to increased levels of lipids, lipoproteins, and apoE in the plasma. However, LPG is not typically associated with extra-renal manifestations of hyperlipoproteinemia, such as arteriosclerosis.
Histological examination confirmed the diagnosis of LPG in the patient, with characteristic features including lipoprotein thrombi in the glomerular capillaries, elevated apoE levels, and the absence of foam cells. The patient’s abnormal lipid profile, characterized by increased plasma levels of TC, TG, LDL-C, and apoE, further supports the diagnosis. The presence of splenomegaly in the patient is an unusual finding in LPG, as the disease is generally considered a renal-limited disorder. The cause of splenomegaly in this case remains unknown, but its association with the APOE mutation warrants further investigation.
Treatment with fenofibrate and perindopril effectively reduced the patient’s plasma lipid levels and improved her renal manifestations. However, previous cases have shown that some patients with LPG may develop renal dysfunction despite treatment, emphasizing the need for careful follow-up.
In conclusion, this study identifies a novel APOE mutation, APOE Shenzhen (p.Arg150Cys), in a Chinese family with one LPG patient and an asymptomatic carrier. The findings suggest that APOE mutations may play a role in the development of LPG, but additional factors are likely involved. Further research is needed to elucidate the mechanisms underlying lipoprotein deposition and the potential extra-renal manifestations associated with APOE mutations.
doi.org/10.1097/CM9.0000000000000050
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