Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy, Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44908814 T>C
Position: (GRCh37/hg19):Chr19:45412071 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was found in a 45-year-old Chinese woman with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Wu et al., 2018; Saito et al., 2020). As is common in LPG patients, she also had hyperlipidemia and elevated levels of ApoE in serum.

The variant was identified by sequencing of the proband’s APOE coding region. It was also found in two of her four siblings: a brother who was on hemodialysis due to kidney malfunction and who had high triglyceride levels in blood, and an asymptomatic sister who had normal levels of protein in urine and only mildly elevated triglycerides in blood. The brother might have had LPG, but it was undiagnosed. His ApoE levels were normal. All carriers were APOE3 homozygotes. Of note, the two brothers who did not carry the mutation had mild hypercholesterolemia.

The variant was absent from 200 local controls and from the gnomAD variant database (v2.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown. However, as noted by Wu and colleagues, it is a proline substitution affecting an amino acid that is near the receptor-binding domain of ApoE and near other variants, also involving proline substitutions, which alter the structural integrity of the protein (Wu et al., 2018). In particular, R163P, R165P, and R176P, all tied to LPG, reduced helical content, exposed hydrophobic surfaces, and caused unfolding of the N-terminal domain (Georgiadou et al., 2013). Moreover, they altered binding to the low-density lipoprotein (LDL) receptor and promoted lipoprotein aggregation. L176 is highly conserved in evolution and is predicted to be involved in the propagation of structural changes in the C-terminal domain, such as those that occur upon lipid binding (Frieden et al., 2015). Consistently, L173P’s PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. 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 Aug 1;25(8):733-740. Epub 2018 Feb 2 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.
3. Georgiadou D, Stamatakis K, Efthimiadou EK, Kordas G, Gantz D, Chroni A, Stratikos E. Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy. J Lipid Res. 2013 Jan;54(1):164-76. Epub 2012 Oct 30 PubMed.
4. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.

Other Citations

1. R163P

Further Reading

No Available Further Reading