A novel apolipoprotein E mutation in a Chinese patient with lipoprotein glomerulopathy

0
0
0

A novel apolipoprotein E mutation (p.Arg150Cys) in a Chinese patient with lipoprotein glomerulopathy

Lipoprotein glomerulopathy (LPG) is a rare inherited kidney disease that primarily affects people of Japanese and Chinese descent. Characterized by fatty clots (lipoprotein thrombi) clogging the tiny filters (glomeruli) in the kidneys, high levels of the protein apolipoprotein E (apoE), and excess protein in the urine (proteinuria), LPG can lead to kidney damage if unmanaged. While APOE gene mutations are known to play a role, some carriers never develop symptoms—leaving gaps in our understanding of what triggers the disease. A 2019 study from researchers at Shenzhen University’s First Affiliated Hospital and Shenzhen Second People’s Hospital sheds new light on this mystery by identifying a novel APOE mutation in a Chinese family with one affected patient and one asymptomatic carrier.

A 21-Year-Old Woman’s Unexpected Journey

The study centers on a 21-year-old Chinese woman who was healthy until a routine prenatal checkup in December 2016. Doctors found moderate proteinuria (0.3–3.5 grams of protein per day), which worsened to severe (up to 5.2 grams per day) during her pregnancy. Four months after giving birth to a healthy daughter, she sought care for ongoing symptoms.

She had no family history of kidney disease or lipid disorders, and her blood pressure was normal (115/77 mmHg). But tests revealed significant issues:

  • Proteinuria: 4.0 grams per day (healthy limit: <0.15 grams).
  • Lipid levels: Total cholesterol (8.53 mmol/L) and LDL (“bad” cholesterol, 6.44 mmol/L) were well above normal.
  • Splenomegaly: An ultrasound showed her spleen was significantly enlarged—rare for a kidney condition.

Her kidneys appeared normal on imaging, but her uric acid was elevated (525.6 mmol/L), and urine samples showed 5–8 red blood cells per high-power field. Tests for hepatitis, autoimmune diseases, and diabetes were negative.

Diagnosis: Lipid Clogs in the Kidneys

To confirm the cause, doctors performed a renal biopsy (a small kidney tissue sample). Key findings included:

  • Glomerular damage: 21 glomeruli were analyzed—2 were scarred, and most had swollen capillaries filled with pale, layered clots.
  • Lipid deposits: Staining with oil red O (which highlights fat) revealed lipid droplets clogging the capillaries.
  • Electron microscopy: Almost all dilated capillaries were blocked by lipid granules and layered vacuoles.
  • Protein markers: The clots strongly stained for apoE and apoB (proteins linked to lipoproteins), confirming LPG.

A Novel Mutation: APOE Shenzhen (p.Arg150Cys)

The team sequenced the APOE gene in the patient, her mother, and two healthy controls. The results were striking:

  • The patient and her mother had a c.308C>T mutation in exon 4 of the APOE gene. This swaps the amino acid arginine for cysteine at position 150, creating a new variant named APOE Shenzhen (p.Arg150Cys).
  • The mother—who carried the same mutation—had no kidney symptoms, normal lipid levels, and no signs of disease. She was a “silent carrier,” proving the mutation alone does not cause LPG.

Treatment Works, But Questions Remain

The patient was treated with fenofibrate (a lipid-lowering drug) and perindopril (to reduce proteinuria). After two months:

  • Total cholesterol dropped from 8.53 to 5.1 mmol/L.
  • Triglycerides fell from 1.56 to 1.33 mmol/L.
  • 24-hour proteinuria decreased from 4.0 to 2.03 grams.
  • Kidney function remained normal.

This aligns with past research showing fibrates are more effective than statins for LPG. However, doctors emphasize long-term follow-up—some patients eventually develop kidney failure.

Key Takeaways from the Study

  1. APOE Shenzhen is a new LPG-linked mutation: The p.Arg150Cys variant adds to a growing list of APOE mutations associated with the disease, including APOE Guangzhou (p.Arg150Pro) identified in 2008.
  2. Genes aren’t everything: The mother’s asymptomatic case shows other factors—like pregnancy hormones (which may have triggered the daughter’s symptoms), lifestyle, or additional genes—play a role in disease development.
  3. Splenomegaly is rare but puzzling: LPG is typically kidney-only, but this patient’s enlarged spleen (seen in just one other LPG case) hints at potential extra-renal effects of APOE mutations.

Conclusion

The study identifies APOE Shenzhen (p.Arg150Cys) as a novel mutation linked to LPG in a Chinese family. While the mutation increases risk, it does not guarantee disease—underscoring the need to explore environmental and genetic modifiers. For patients with LPG, lowering lipids with fibrates can improve symptoms, but ongoing research is critical to unlock why some carriers stay healthy.

The study was led by Ming Ku, Cai Tao, Yuan Cheng, and Qi-Jun Wan from the Department of Nephrology at Shenzhen University’s First Affiliated Hospital and Shenzhen Second People’s Hospital, with contributions from An-An Zhou of Shenzhen Chi Biology Technology Co., Ltd. It followed the Declaration of Helsinki, was approved by Shenzhen University’s Ethics Committee, and received funding from the Health and Family Planning Commission of Shenzhen Municipality (grant No. 201605008).

Ku M, Tao C, Zhou AA, Cheng Y, Wan QJ. A novel apolipoprotein E mutation (p.Arg150Cys) in a Chinese patient with lipoprotein glomerulopathy. Chin Med J 2019;132:237–239. https://doi.org/10.1097/CM9.0000000000000050
Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis 1989;13:148–153. https://doi.org/10.1016/S0272-6386(89)80134-9
Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis 2006;47:199–211. https://doi.org/10.1053/j.ajkd.2005.10.017
Wu H, Yang Y, Hu Z. The novel apolipoprotein E mutation ApoE chengdu (c.518T>C, p.L173P) in a Chinese patient with lipoprotein glomerulopathy. J Atheroscler Thromb 2018;25:733–740. https://doi.org/10.5551/jat.41996
Hu Z, Huang S, Wu Y, Liu Y, Liu X, Su D, et al. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int 2014;85:416–424. https://doi.org/10.1038/ki.2013.335
Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, et al. A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant 2008;23:381–384. https://doi.org/10.1093/ndt/gfm735
Kinomura M, Sugiyama H, Saito T, Matsunaga A, Sada KE, Kanzaki M, et al. A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant 2008;23:751–756. https://doi.org/10.1093/ndt/gfm675
Chen S, Liu ZH, Zheng JM, Zhang X, Li LS. A complete genomic analysis of the apolipoprotein E gene in Chinese patients with lipoprotein glomerulopathy. J Nephrol 2007;20:568–575. PMID: 17918142
Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF, et al. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol 2008;28:347–353. https://doi.org/10.1159/000111828
Tudorache IF, Trusca VG, Gafencu AV. Apolipoprotein E – A multifunctional protein with implications in various pathologies as a result of its structural features. Comput Struct Biotechnol J 2017;15:359–365. https://doi.org/10.1016/j.csbj.2017.05.003

Was this helpful?

0 / 0