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      Apolipoprotein E Mutation and Double Filtration Plasmapheresis Therapy on a New Chinese Patient with Lipoprotein Glomerulopathy

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          Background/Aims: Lipoprotein glomerulopathy (LPG) is a rare hereditary disease. In this study, we investigated the apoE mutation and the role of double filtration plasmapheresis therapy (DFPP) on a new Chinese patient with LPG. Methods: Renal biopsy was performed on this patient to allow a definitive diagnosis. The mutations in the coding sequence of apoE and the hereditary pedigree of this patient were investigated by DNA sequencing. The patient was treated with DFPP, and clinical parameters before and after DFPP were compared. Results: Two missense mutations were found in this patient: Cys112Arg and Arg25Cys. Arg25Cys was previously designated as APOE Kyoto. Family genotyping showed that Cys112Arg and Arg25Cys mutation were transmitted through his father and his mother, respectively. The patient's parents are healthy so far to date. Possibly there was a dose effect on apoE mutation induced LPG. Furthermore, DFPP treatment was first used on this patient and led to dramatic changes: Proteinuria and apo E values declined, and hemoglobin level increased significantly. Conclusion: APOE Kyoto mutation was found in a new Chinese patient with LPG, accompanied by Cys112Arg. More cases and further functional experiments are needed to investigate the role of these two mutations together in LPG. DFPP is an effective therapeutic modality for improving NS in patients with LPG.

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          Most cited references 21

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          A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

          Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
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            Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia.

             K Yoshinaga,  K Kudo,  H. Sato (1989)
            An unusual nephropathy presumably induced by abnormal lipid metabolism is described in a 57-year-old woman who presented with proteinuria and edema. Histology at renal biopsy was characterized by marked dilatation of capillary lumina. Sudan staining and electron microscopy demonstrated lipid droplets occupying the capillary lumina. The patient had no particular clinical symptoms of lipidosis, but hyperlipoproteinemia similar to type III was suggested by lipid profiles. The nephropathy is thought to be an inherited disorder because proteinuria was detected in her sisters and similar renal histology and lipid profile were observed in one of her sisters. This is believed to be the first detailed report of glomerular lipoprotein thrombi.
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              A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy.

              Lipoprotein glomerulopathy (LPG) is characterized by intraglomerular lipoprotein thrombosis and high plasma concentrations of apolipoprotein (apo) E. An apo E variant, apo E2 (Arg145Pro) Sendai, was recently identified in three patients with LPG. We detected a novel point mutation in the apo E gene in a patient with LPG, and we characterized the mutant apo E. The propositus was a 32-year-old male patient on maintenance hemodialysis because of LPG. The mutation was detected by sequencing of genomic DNA from the patient and was confirmed by restriction fragment length polymorphism (RFLP) with Aor51HI. Recombinant apo E2 (Arg25Cys) Kyoto and normal apo E3 were expressed from COS-1 cells. Low-density lipoprotein (LDL) receptor-binding activities of the variants were determined in an in vitro competition assay. The propositus had the apo E phenotype E2/E4, as determined by isoelectric focusing, and the genotype epsilon3/epsilon4, as determined by RFLP with HhaI. Sequence analysis of amplified DNA showed a C to T transition, changing the codon for residue 25 from arginine to cysteine. The proband was a heterozygous carrier for apo E2 (Arg25Cys) Kyoto. A family study showed that the mother was a heterozygous carrier of apo E2 Kyoto and had dysbetalipoproteinemia, but no LPG. The pathophysiological effect of this mutation was investigated in vitro by binding studies of recombinant apo E2 Kyoto to LDL receptors on human fibroblasts. The ability of recombinant apo E2 Kyoto to displace LDL was reduced to 10% compared with recombinant apo E3. Apo E2 (Arg25Cys) Kyoto is a novel mutation of apo E that is etiologically related to LPG. However, our case indicates that the development of LPG may involve other genetic or environmental factors. Furthermore, our data suggest that arginine-25 of apo E plays an important functional role by influencing the receptor-binding ability of apo E.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                November 2014
                19 September 2014
                : 39
                : 4
                : 330-339
                aDepartment of Urology; bDepartment of Emergency, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology; cDepartment of Nephrology, PLA 161 th hospital, Wuhan 430010; dDepartment of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China
                Author notes
                *Jing Xiong, M.D, Ph.D., Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong, University of Science & Technology, Wuhan, 430022 (China), Tel. (86) 85726713, E-Mail
                355810 Kidney Blood Press Res 2014;39:330-339
                © 2014 S. Karger AG, Basel

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                Page count
                Pages: 10
                Original Paper


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