Lipoprotein Glomerulopathy

A number sign (#) is used with this entry because of evidence that lipoprotein glomerulopathy can be caused by heterozygous mutation in the APOE gene (107741).

Description

Lipoprotein glomerulopathy is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries (Saito et al., 2006). It mainly affects people of Japanese and Chinese origin; in these populations, it is associated with mutations in the gene that encodes apolipoprotein E (APOE; 107741). The disorder had rarely been described in Caucasians.

Clinical Features

Lipoprotein glomerulopathy is characterized by abnormal lipoprotein deposition in the glomeruli, usually with lipoprotein thrombi distending and occluding the glomerular capillary lumina, a variable degree of mesangial proliferation, dysbetalipoproteinemia, and high levels of APOE and APOE2/3 phenotype in most cases (Matsunaga et al., 1999). It has been described predominantly in Japanese and Chinese (Rovin et al., 2007).

Rovin et al. (2007) described 2 European American families in each of which a single male presented with edema and proteinuria in the nephrotic range. In both, kidney biopsy showed an amorphous material that stained positive for neutral lipids in almost all glomerular capillaries. One clinically unaffected heterozygous female, an aunt of one of the probands, showed in a nephrectomy specimen obtained for therapy of renal cell carcinoma a glomerulus with dilated capillary loops containing amorphous material similar to that found in the patients with lipoprotein glomerulopathy.

Molecular Genetics

Oikawa et al. (1997) identified 3 Japanese patients with lipoprotein glomerulopathy who were heterozygous for an arg145-to-pro mutation in APOE (R145P; 107741.0032). The authors designated this variant 'APOE Sendai.'

Matsunaga et al. (1999) reported a Japanese man with lipoprotein glomerulopathy who carried an arg25-to-cys mutation in APOE (R25C; 107741.0033). The patient's mother, a heterozygous carrier, had dysbetalipoproteinemia but no lipoprotein glomerulopathy. Matsunaga et al. (1999) termed this variant 'APOE Kyoto.'

In 2 unrelated American men of European ancestry with lipoprotein glomerulopathy, Rovin et al. (2007) detected an R25C substitution in APOE. Heterozygous female carriers were clinically unaffected. Rovin et al. (2007) remarked that the APOE Kyoto mutation appears to be sufficient to lead to glomerular lipoprotein deposition but not to clinical lipoprotein glomerulopathy. 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. Impaired LPL binding was also seen with APOE Sendai (Ishigaki et al., 2000). Rovin et al. (2007) suggested 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.