Abbreviations: NPHS2: nephrosis 2, steroid-resistant ; SRNS: steroid-resistant nephrotic syndrome
Introductory paragraphNephrotic syndrome is the consequence of damage to the glomerular filtration barrier, and it refers to the clinical symptoms of heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. The steroidresistant form of nephrotic syndrome (SRNS) has a poor prognosis, as it often leads to endstage renal disease (ESRD) 1,2 . Mutations in more than 20 genes have been identified in monogenic forms of SRNS, most of which encode podocyte proteins3-5. NPHS2, encoding podocin, is the most frequently mutated of these genes and is responsible for 12-18% of SRNS cases 3,6,7 . Podocin accumulates in dimeric or oligomeric forms in lipid raft microdomains at the podocyte slit diaphragm, which is the key component of the glomerular filtration barrier. On the basis of its predicted structure, podocin belongs to the stomatin protein family, with a hairpin-like intramembrane loop and intracellular N and C termini. The C-terminal portions of both stomatin and podocin are responsible for dimerization 6,[8][9][10][11][12] .Individuals with NPHS2 mutations typically develop SRNS before 6 years of age and progress to ESRD during their first decade of life6. The phenotype can be less severe in the setting of a trans association of an NPHS2 mutation and the polymorphism c.686G>A (p.Arg229Gln, rs61747728), a genotype we hereafter denote as p.[Arg229Gln];[mut] that causes SRNS with a median age at diagnosis of 13 years (range, 0-39 years) and progression to ESRD by 26 years (range, 10-50 years) 7,[13][14][15][16][17][18] . Nevertheless, the p.Arg229Gln variant in the homozygous state does not cause SRNS 19,20 .On the basis of the 15× higher allele frequency of p.Arg229Gln (357/13,006, 2.7%) than the cumulative allele frequency of the known disease-causing variants 13-18,21-43 (24/13,006, 0.18%)
