Nphs2, which codes for podocin, is a gene of great significance. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. It plays a crucial role in maintaining the integrity of the glomerular filtration barrier, and its proper function is essential for normal kidney function [1,2,4,7]. Mutations in Nphs2 can disrupt this function, leading to various kidney-related pathologies.

Mutations in Nphs2 are the most frequent genetic cause of steroid-resistant nephrotic syndrome (SRNS) [1]. In both pediatric and adult patients, homozygous or compound heterozygous mutations commonly lead to SRNS before the age of 6 years and often progress rapidly to end-stage kidney disease, with a low prevalence of recurrence after renal transplantation [3]. Screening for Nphs2 mutations in sporadic and familial cases of SRNS has documented a mutation detection rate of 45-55% in families and 8-20% in sporadic cases, depending on the groups and phenotypes considered [2]. The R229Q variant of Nphs2, which is more common among European-derived populations, shows an association with a trend toward increased focal segmental glomerulosclerosis risk in these populations, while not being associated with focal segmental glomerulosclerosis in the US population of African descent [4]. Functional studies demonstrated that most mutants involving the stomatin domain are retained in the endoplasmic reticulum, and the R229Q polymorphism shows an altered interaction with nephrin affecting the stability of the functional unit [2].

In conclusion, Nphs2 is vital for the normal function of the glomerular filtration barrier. Its mutations are strongly associated with steroid-resistant nephrotic syndrome and related kidney diseases. Understanding the role of Nphs2 through genetic studies, especially those on its mutations, provides valuable insights into the pathogenesis of these kidney disorders, which may potentially guide the development of more targeted therapeutic strategies [1,2,3,4,5,6,8,9].