NPHS2 Functional Variant (R229Q) in Primary Nephrotic Syndrome: A Study from South India

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Nephrotic Syndrome (NS) comprises of Heavy Proteinuria, Hypo Albuminemia, Edema and Hyperlipidemia.  The worldwide prevalence of NS was reported to be 12-16 per 100,000 individuals; epidemiological evidence of a higher incidence of NS in children from South Asia. The present study focuses on the contribution of a common functional polymorphism R229Q (rs61747728) of NPHS2 gene towards NS susceptibility, the underlying histopathology and steroid response in south Indian population. Blood samples from a total of 484 individuals (234 cases and 250 controls) were subjected to molecular analysis using PCR-RFLP method.

Data analysis revealed mutant A allele frequency to be 2.8% in normal healthy individuals and 11% in patients with NS, conferring a fourfold increased risk towards disease susceptibility. Furthermore, the occurrence of A allele was 2.55% and 23.65% in mild (MCD) and severe (FSGS) histopathology patient groups respectively. However, with respect to treatment response no significant variation was noted in the frequency of mutant allele in steroid sensitive and steroid resistant group of patients. Computational predictions of the potential impact of this variant were found to be possibly damaging. Thus R229Q variant appears to be a probable contributing factor towards NS pathogenesis among south Indians.


Nephrotic syndrome (NS) is a malfunction of the kidney glomerular filter and is one of the commonest causes of renal problems in children encountered by

nephrologists (1). The characteristic features of NS are heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia (2). The cause of proteinuria is due to injury to the function or structure of glomerular filtration barrier. The estimated annual incidence of NS ranges from 2-7 per 100,000 children and

prevalence from 12-16 per 100,000 worldwide. There is epidemiological evidence of a higher incidence of NS in children from South Asia (3). It appears to be a clinically heterogeneous condition characterized by histological variants (4) and different genetic backgrounds (5, 6) with recessive and dominant inheritances. For these patients the therapeutic option is a standard steroid therapy and on the basis of the patient’s response to steroid therapy, it is divided into Steroid-sensitive Nephrotic Syndrome (SSNS) and Steroid-resistant Nephrotic Syndrome (SRNS) which may progress to End-stage Renal Disease (ESRD) (7), which is the final result of various etiologies. Numerous prognostic indicators leading to ESRD have been extensively studied, of which genetic factors remain a subject of great concern (8)

The primary defect in NS is an injury to the glomerular basement membrane (GBM) which is responsible for the size and charge-selective properties of renal filter. One of the key components of GBM are podocytes. Podocytes are highly specialized, terminally differentiated cells with cytoplasmic extensions, foot processes. These cells have an important role in size and charge selective permeability, but also in synthesizing and maintaining the GBM (9). Characterization of mutations in the genes coding for podocyte proteins in patients with inherited nephrotic syndrome has been a breakthrough in both molecular and clinical research (10).

Podocin protein, a member of the stomatin protein family is encoded by NPHS2 gene which is located at chromosome 1q25-q31 and was first mapped by linkage analysis in families with autosomal recessive SRNS. NPHS2 coding region is 1,149 bp in length, has 8 exons and encodes the 42kD integral membrane protein podocin which is expressed in both fetal and mature kidney. Podocin recruits other important podocyte proteins like nephrin and CD2AP in lipid rafts ensuring a stable and proper functioning filtration barrier (11). In human, NPHS2 mutations, are mainly associated with autosomal recessive SRNS, but were also found in sporadic cases of SRNS patients.  Mutated podocin may cause disturbance in recruiting nephrin to the plasma membrane, which is comparable with the lack of nephrin in the slit membrane found in podocin deficient mice (12).

Tsukaguchi et al. studied the R229Q variant that is a common polymorphism occurring at an increased frequency in association with late onset FSGS. They used pull-down experiments with anti-podocin antibodies and found a reduced binding to nephrin in the presence of this polymorphism compared with the wild protein. It was put forward that this common variant may contribute to glomerulosclerosis in association with other mutant NPHS2 alleles or acting in synergism with other factors (13).

The present study focuses on the contribution of common polymorphism R229Q (rs61747728) towards susceptibility to NS, underlying histopathology and steroid response in south Indian population. This kind of study holds importance in defining the molecular basis for the disease.


This is one of the largest studies of Asia and our data with respect to allele frequency and the insilico analysis supports the role of the R229Q substitution in susceptibility and severity of NS. It appears to be a good contributing factor in disease pathogenesis in our population. We showed that it may not affect the manner of podocin dimerization however, it was noted to have possibly destabilizing effect on the podocin protein, thereby reflect the probable influence of R229Q in the pathogenesis of NS. As it is a common polymorphism, extensive studies in different ethnic populations are warranted in order to understand the gene-gene as well as gene-environment interactions for this particular polymorphism in primary and secondary kidney disease


The authors wish to thank the Indian Council of Medical Research, New Delhi for the financial support

Conflict of interest

The authors declare that there is no conflict of interest.


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