Minimal change nephrotic syndrome and prohibitin-2 gene polymorphism.
BACKGROUND
Patients with minimal change nephrotic syndrome (MCNS) often also have allergic diseases. Abnormalities of Th2-derived cytokines and T-cell functions contribute to development of these diseases. On the other hand, imbalances between reactive oxygen species (ROS) and antioxidants have been implicated in MCNS and progression of atopic dermatitis. ROS, produced mainly within mitochondria, subject cells to oxidative stress, while prohibitin 2 protects mitochondria by increasing tolerance to ROS. Additionally, podocin, a member of the slit diaphragm protein complex, contains PHB-like domain that serves as a signaling platform regulating podocyte function through associated transmembrane proteins.


METHODS
Then, we performed exome sequencing analysis in five patients with frequently relapsing their MCNS associated with allergic disease and serum IgE concentrations of 2000 IU/L or higher.


RESULTS
We detected a heterozygous prohibitin 2 polymorphism, c.873-3_873-2 delCA (rs111523336), in 1 patient. This mutation in exon 9 caused frameshifts in regions connected to splicing sites, where they could disrupt transcription of prohibitin 2. Frequency of this polymorphism in exon 9 is 7.3% among Japanese. Increase in peripheral blood ROS even MCNS remission state suggests the heterozygous prohibitin 2 variant may contribute to give more susceptibility towards the recurrence of MCNS as well as atopic skin disease. This increase may have progression of atopic dermatitis, which sometimes heralded.


CONCLUSIONS
The prohibitin-2 polymorphism may reduce ROS tolerance in glomerular epithelium and led to high local exposure to ROS, increasing permeability of the glomerular basement membrane to result in proteinuria. Imbalance between ROS and antioxidants together with failure of signal transduction in the glomerular slit membrane caused by prohibitin 2 abnormality could have contributed to nephrotic syndrome in our patients. Prohibitin 2 analysis is needed in additional MCNS patients with concomitant allergic disease.
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Keisuke
K
Sugimoto
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Tomoki
T
Miyazawa
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Kohei
K
Miyazaki
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Hidehiko
H
Yanagida
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Takuji
T
Enya
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Hitomi
H
Nishi
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Norihisa
N
Wada
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan.
Mitsuru
M
Okada
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan. tsukasa@med.kindai.ac.jp.
Tsukasa
T
Takemura
D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016207:Cytokines / Q000097:blood; D004252:DNA Mutational Analysis; D003876:Dermatitis, Atopic / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D059472:Exome; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D009402:Nephrosis, Lipoid / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D018384:Oxidative Stress; D010641:Phenotype; D011110:Polymorphism, Genetic; D000091402:Prohibitins; D011507:Proteinuria / Q000235:genetics / Q000276:immunology; D017382:Reactive Oxygen Species / Q000097:blood; D012008:Recurrence; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D000073359:Exome Sequencing
D015415:Biomarkers; D016207:Cytokines; D005819:Genetic Markers; C000717328:PHB protein, human; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D007073:Immunoglobulin E
Antioxidants; Atopic dermatitis; Minimal change nephrotic syndrome; Mutations; Prohibitin; Reactive oxygen species