An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations.
This study demonstrates that the urinary proteome of pediatric RCAD patients differs from autosomal dominant polycystic kidney disease (PKD1, PKD2), congenital nephrotic syndrome (NPHS1, NPHS2, NPHS4, NPHS9) as well as from chronic kidney disease conditions, suggesting differences between the pathophysiology behind these disorders.
This study demonstrates that the majority of CNS cases (67%, 8/12 patients) are caused by genetic defects, and the NPHS1 mutation is the most common cause of CNS in Chinese patients.
To date, however, the effect of CNS-associated NPHS1 variants on nephrin phosphorylation remains to be determined, which hampers genotype-phenotype correlations.
In addition, 3D organoid glomeruli from a congenital nephrotic syndrome patient with compound heterozygous NPHS1 mutations reveal reduced protein levels of both NEPHRIN and PODOCIN.
The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS.
The main objective of this study was to perform the analysis of the NPHS1 gene in patients with congenital nephrotic syndrome in order to determine the molecular cause of the disease.
The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS.
Furthermore, we conducted functional analysis of NPHS1 mutations in Japanese patients with congenital nephrotic syndrome using this simple method, which revealed that all pathogenic mutations impaired trafficking to the protein plasma membrane.
Mutations in the NPHS1 gene that encodes nephrin cause congenital nephrotic syndrome (CNS), which is characterized by the loss of the SD and massive proteinuria.
Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease caused by mutations in a major podocyte protein, nephrin.
Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible for childhood-onset steroid-resistant nephrotic syndrome in European populations.
The prototype of congenital nephrotic syndrome is congenital nephrotic syndrome of Finnish type (CNF, OMIM #602716), which is caused by loss-of-function mutations of the nephrin gene (NPHS1).
Classically, infants with mutations in NPHS1, which encodes nephrin, present with nephrotic syndrome within the first 3 mo of life (congenital nephrotic syndrome of the Finnish-type), and children with mutations in NPHS2, which encodes podocin, present later with steroid-resistant nephrotic syndrome.