Correspondence

APOE Kyoto Mutation in European Americans with Lipoprotein Glomerulopathy

N Engl J Med 2007; 357:2522-2524December 13, 2007

Article

To the Editor:

Lipoprotein glomerulopathy is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries.1 It mainly affects people of Japanese and Chinese origin; in these populations, it is associated with novel mutations in APOE, the gene that encodes apolipoprotein E.2 To date, only two cases of lipoprotein glomerulopathy have been documented in whites (both of whom were European), but genotyping was not performed in these patients.

We have identified the disease in two unrelated American men of European ancestry who presented with edema and proteinuria in the nephrotic range. The results of kidney biopsy in both patients were similar and showed an amorphous material that stained positive for neutral lipids occluding almost all glomerular capillaries (Figure 1A and 1BFigure 1Kidney-Biopsy Specimens, Genomic Sequencing, and Family Pedigrees of Patients with the APOE Kyoto Mutation.).

APOE was sequenced with the use of genomic DNA from both patients and their available family members. Both patients had a heterozygous C→T transition in exon 3 of APOE that changed the amino acid at position 25 of the mature protein from arginine to cysteine (Figure 1D). Family genotyping showed that this mutation was transmitted through the maternal side of each family (Figure 1E). Although several female family members were heterozygous carriers of Arg25Cys, none had clinical evidence of lipoprotein glomerulopathy. However, a nephrectomy specimen that was available for examination from one unaffected carrier showed amorphous material that was identical in appearance to lipoprotein thrombi in approximately 1% of glomeruli (Figure 1C).

To estimate the occurrence of the Arg25Cys mutation in the American population, genotyping was performed on archived DNA from 86 European Americans and 95 African Americans who had no evidence of lipoprotein glomerulopathy. No sample showed the mutation.

A heterozygous Arg25Cys mutation was originally described in a Japanese man with lipoprotein glomerulopathy and was designated as APOE Kyoto.3 The patient's mother was an unaffected heterozygous carrier. Four other patients with lipoprotein glomerulopathy and the APOE Kyoto mutation have been described. Of these patients, all were Asian, three were men, and three had a heterozygous mutation; the mutational status of one patient was not stated.

The APOE Kyoto mutation appears to be sufficient to lead to glomerular lipoprotein deposition but not to clinical lipoprotein glomerulopathy (Figure 1C). Apolipoprotein E may accumulate in glomerular capillaries because the mutation diminishes the capacity of apolipoprotein E to bind to the low-density lipoprotein (LDL) receptor and also decreases its uptake by endothelial cells.3,4 Impaired LDL-receptor binding is also seen in patients with APOE Sendai, another variant associated with lipoprotein glomerulopathy.5

On the basis of the difference in the extent of glomerular involvement between patients with lipoprotein glomerulopathy (Figure 1A) and an unaffected carrier (Figure 1C), we suggest that APOE Kyoto carriers in whom the disease develops may have a second defect that reduces clearance of abnormal lipoprotein through pathways that are independent of the LDL receptor, which allows for excessive accumulation of thrombi and the development of clinical kidney disease. Given the apparent male predominance of lipoprotein glomerulopathy with APOE Kyoto, men may be at increased risk for the disease.

Brad H. Rovin, M.D.
Daniel Roncone, D.O.
Alison McKinley, B.A.
Tibor Nadasdy, M.D.
Ohio State University College of Medicine, Columbus, OH 43210
rovin.1@osu.edu

Stephen M. Korbet, M.D.
Melvin M. Schwartz, M.D.
Rush University Medical Center, Chicago, IL 60612

5 References

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Citing Articles (1)

Citing Articles

1. 1

   A. S. Bomback, H. Song, V. D. D'Agati, S. D. Cohen, A. Neal, G. B. Appel, B. H. Rovin. (2010) A new apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrology Dialysis Transplantation 25:10, 3442-3446
   CrossRef