Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy, Cardiovascular Disease, Blood Lipids/Lipoproteins
Reference Assembly: GRCh37/hg19
Position: Chr19:45412073_45412124 CAGAAGCGCCTG . . . GCCGAGCGCGGC>-
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: CAG AAG CGC CTG . . . GCC GAG CGC GGC to -
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 57-year-old Japanese man with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Ando et al., 1999; Saito et al., 2020). The patient also had systemic atherosclerosis, a condition not usually tied to LPG. Compared with controls, he had low levels of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, but elevated levels of intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) cholesterol. In addition, ApoE levels were increased.

A genetic abnormality was first suspected when the patient’s ApoE proteins were analyzed by isoelectric focusing. In addition to a band migrating to the position of the common ApoE isoform ApoE3, the authors observed a faster migrating band, ApoE1. After DNA genotyping revealed the patient was homozygous for the APOE3 allele, the authors sequenced exons 3 and 4, and discovered that one of the alleles had a deletion of 54 base pairs resulting in the in-frame loss of 18 amino acids. This mutation was also found in one of the proband’s daughters. At age 31, she had no signs of renal or cardiovascular disease.

Biological Effect

The biological effect of this variant is unknown, but the authors speculated that the deletion of this region likely affects cell surface binding, particularly since it includes R176, whose charge is thought to influence the conformation of ApoE’s nearby receptor-binding region (Ando et al., 1999).

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References

Paper Citations

1. Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, Oikawa S, Saito T, Nihei H. A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 1999 Oct;56(4):1317-23. PubMed.
2. Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S, Muso E. Apolipoprotein E-related glomerular disorders. Kidney Int. 2020 Feb;97(2):279-288. Epub 2019 Nov 22 PubMed.

Further Reading

No Available Further Reading