Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia

Atherosclerosis has been rarely reported among patients with LPG.

“Atherosclerosis has been rarely reported among patients with LPG [18], although dyslipidemia commonly persisted.”

Mutated apoE has been proposed as a factor outside the kidney crucial for LPG pathogenesis because LPG is related to inherited apoE gene mutations acting dominantly with incomplete penetrance.

“One such factor has been proposed to be mutated apoE, because LPG has been related with inherited mutations within the apoE gene that act in a dominant way but with incomplete penetrance (1,2,5,6).”

The majority of LPG-associated apoE mutations are located in the helical N-terminal domain of apoE.

“The majority of LPG-associated apoE mutations are located in the helical N-terminal domain of the molecule (5,6).”

Most LPG patients have been reported to present elevated plasma apoE levels, while normalization or reduction of apoE levels following various treatments results in remission or improvement of the disease.

“Most of the LPG patients have been reported to present elevated plasma apoE levels (5, 6, 23-25), while it has been observed that normalization or reduction of apoE levels following various treatments (e.g., lipid-lowering treatments with fenofibrate or protein A immunoadsorption) result in remission or improvement of the disease (24,25,47).”

APOE gene mutations due to amino acid duplication are rare.

“APOE gene mutations due to amino acid duplication are rare”

Most APOE gene mutations causing LPG are missense mutations due to substitution of amino acid residues around the LDL receptor-binding region.

“Most of them are missense mutations due to the substitution of amino acid residues around the low-density lipoprotein (LDL) receptor-binding region.”

The APOE gene mutation due to duplicated amino acid residues was included among APOE gene mutations causing LPG.

“In addition , the APOE gene mutation due to duplicated amino acid residues was included there [2].”

The APOE mutation sites in LPG, including APOE Kanto, are ordinarily found around the LDL receptor domain.

“The APOE mutation sites in LPG, including APOE Kanto, are ordinarily found around the LDL receptor domain”

Missense mutations in LPG were often arginine-to-proline substitutions like APOE Sendai, resulting in structural changes in the apo E molecule.

“the missense mutations were often arginine-to-proline substitutions like APOE Sendai [2], resulting in structural changes in the apo E molecule.”

More than 95% of type III hyperlipoproteinemia individuals carry homozygous APOE2 mutation.

“more than 95% of type III hyperlipoproteinemia individuals carry homozygous APOE2 mutation [14].”

Most homozygous APOE2 carriers are normolipidemic and less than 10% show type III hyperlipoproteinemia.

“most of homozygous APOE2 carrier are normolipidemic and less than 10% of them show type III hyperlipoproteinemia [14, 15].”

More than 10 types of LPG-related mutations have been identified in APOE showing autosomal dominant inheritance patterns with incomplete penetrance.

“More than 10 types of LPG‐related mutations have been identified in APOE showing autosomal dominant inheritance patterns with incomplete penetrance (Matsunaga & Saito, 2014).”

Systemic manifestations of type III hyperlipidemia, such as xanthoma, are hardly seen in patients with LPG.

“The systemic manifestations of type III hyperlipidemia, such as xanthoma, are hardly seen in patients with LPG (Matsunaga & Saito, 2014).”

Unlike in type III HLP, patients with LPG do not develop palmar linear xanthomas or tendon xanthomas, and they have a low risk of complications related to atherosclerosis.

“Unlike in type III HLP, however, patients with LPG do not develop palmar linear xanthomas or tendon xanthomas, and they have a low risk of complications related to atherosclerosis70).”

Five variants in helix 4 that were not in the LDL receptor binding site-APOE Kanto (Asp151dupAsp), APOE Las Vegas (Ala152Asp), APOE Chengdu (Leu155Pro), APOE1 (156_173del), and APOE Osaka/Kurashiki (Arg158Pro)-were reported to cause LPG.

“Five variants in helix 4 that were not in the LDL receptor binding site were identified (Fig.5), but were reported to cause LPG, namely, APOE Kanto (Asp151dupAsp)70, 80), APOE Las Vegas (Ala152Asp)81), APOE Chengdu (Leu155Pro)82), APOE1 (156_173del)83), and APOE Osaka/Kurashiki (Arg158Pro)84, 85).”

APOE Kyoto (Arg25Cys) has been reported as the most common variant in LPG worldwide, including southwestern China, Japan, France, and the United States.

“Moreover, APOE Kyoto (Arg25Cys)87) has been reported as the most common variant in LPG worldwide, including southwestern China, Japan, France, and the United States70, 94).”

Patients with LPG often exhibit abnormalities in lipid metabolism similar to type III hyperlipoproteinemia, elevated concentrations of ApoE, and varying degrees of proteinuria.

“Patients with LPG often exhibit abnormalities in lipid metabolism (similar to type III hyperlipoproteinemia) and elevated concentrations of ApoE, as well as varying degrees of proteinuria.”

The main pathological feature of LPG is the presence of a large amount of lipoprotein thrombi in the glomerulus.

“The main pathological feature is the presence of a large amount of lipoprotein thrombi in the glomerulus.[6]”