Lipoprotein Glomerulopathy: A New Apolipoprotein E Mutation With Enhanced Glomerular Binding

The APOE mutation NM_000041.4:c.494G>C (p.Arg165Pro) is in exon 4 of APOE and is known as APOE Chicago mutation.

“which is in the exon 4 of the APOE gene and also known as APOE Chicago mutation, a rare mutation of LPG.”

Mutated ApoE exhibits increased affinity to endothelial cells, as found in APOE Kyoto (Arg25Cys) and APOE Chicago (Arg147Pro), which helps drive lipoproteins to deposit primarily in the capillary lumina of glomerulus and eventually cause LPG.

“Moreover, mutated ApoE also exhibits increased affinity to endothelial cells, as found in APOE Kyoto (Arg25Cys) and APOE Chicago (Arg147Pro), which help drive lipoproteins to deposit primarily in the capillary lumina of glomerulus and eventually cause LPG [7, 19].”

The APOE Chicago mutation has only been reported in five patients/families so far.

“which has only been reported in five patients/families so far and their characteristics are summarized in Table 1.”

APOE-Chicago was first reported in a male Mexican-American patient and later in a Japanese female patient.

“APOE‐Chicago was also first reported in Chinese LPG patients which was first reported in a male Mexican‐American patient (Sam et al., 2006) and later in a Japanese female patient (Kodera et al., 2017).”

Mutated apoE exhibits enhanced binding to glomerular capillaries, which might be a part of the pathogenic mechanism of LPG.

“These studies suggest that mutated apoE exhibits enhanced binding to glomerular capillaries, which might be a part of the pathogenic mechanism of LPG.”

The substitution of proline has been reported in 5/12 variants in the LDL receptor-binding hotspot region, including apoE Sendai, apoE Chicago, apoE Guangzhou, apoE Osaka/Kurashiki, and apoE Chengdu.

“Interestingly, the substitution of proline has been reported in 5/12 variants in this hotspot region, including apoE Sendai (p.R163P)4), apoE Chicago (p.R165P)11), apoE Guangzhou (p.R168P)12), apoE Osaka/Kurashiki (p.R176P)13, 14), and apoE Chengdu (p.L173P).”

Nearly half of reported ApoE mutations in lipoprotein glomerulopathy occurred in the LDL-receptor binding site, and these mutations might result in reduced binding capacity of ApoE protein to the LDL receptor.

“Nearly half of mutations occurred in the LDL-receptor binding site (LRBS), such as ApoE Sendai (Arg145Pro) [2], ApoE Chicago (Arg147Cys) [16], ApoE Guangzhou (Arg150Pro)[17], ApoE Modena (Arg 150Cys) [11], ApoE Okayama (Arg150Gly) [18], ApoE Tokyo (Del 141-143) [19], and ApoE Maebasi (Del 142-144). These mutations might result in reduced binding capacity of ApoE protein to LDL receptor.”

ApoE Chicago (Arg147Pro) has been reported in the United States.

“apoE Chicago (Arg147Pro) 8) and apoE Guangzhou (Arg150Pro) 9) have been reported in the United States and China, respectively.”

ApoE-Sendai corresponds to apoE phenotype E2 on IEF.

“Although apoE-Chicago [7] and apoE-Sendai [2] are the representative mutations in LPG indicating phenotype E2 on IEF”

Sam et al. demonstrated enhanced binding of apoE-Chicago to glomerular capillaries in a patient with LPG.

“Sam et al. [7] demonstrated enhanced binding of apoE-Chicago to glomerular capillaries in a patient with LPG.”

Only 10 cases of LPG (including this one) have been reported from North America, and previously only 5 included gene sequencing.

“Only 10 cases of LPG (including this one) have been reported from North America,2,18,21–26 and previously only 5 of these included gene sequencing: 3 APOE Kyoto,18,23 1 APOE Chicago,22 1 APOE Las Vegas.25”