Familial Focal Segmental Glomerulosclerosis With Late-Onset Presentation and R229Q/R291W Podocin Mutations

Abstract

Introduction: Pathogenic variants in different genes have been described as involved in the development of familial focal segmental glomerulosclerosis (FSGS). A more precise genotype-phenotype correlation would be helpful to better characterize the clinical and laboratorial manifestations of this disease, as well as response to treatment. We analyzed podocin (NPHS2) gene variants in 50 members of four generations of a family with late-onset presentation of glomerular disease. Results and Discussion: The NPHS2 gene variants R229Q and/or R291W were detected in several individuals, and the phenotype of FSGS with progressive loss of renal function was observed in all the family members carrying both mutations simultaneously. Patients manifested ongoing proteinuria over the years and progressive loss of renal function, which in three women culminated in renal replacement therapy by the 4th decade of life. In two affected patients with nephrotic syndrome, remission was not reached by the use of corticosteroids and other immunosuppressive drugs. The R229Q variant was pathogenic only when trans-associated with specific mutations, as the R291W variant in this family. Conclusion: Coexistence of the two NPHS2 variants R229Q and R291W in compound heterozygosis was a determinant of the FSGS phenotype. The presence of these variants alone in heterozygosis did not cause significant proteinuria.

NPHS1 and NPHS2 Variants Associated with Early-Onset Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome

“…and 310 has been reported in three children who developed ESKD [49]. More recently, Righetti, et al [50]. concluded that compound heterozygous R229Q or R291W variants might be associated with the FSGS phenotype, but neither heterozygous variant was associated with significant proteinuria.…”

Cytoskeleton Rearrangement in Podocytopathies: An Update

“…Nephrin directly interacts with podocin (encoded by NPHS2 ) to transport nephrin to the plasma membrane [ 37 ]. NPHS2 mutations lead to the misfolding and mislocalization of podocin and interrupt the proper trafficking of nephrin, causing FSGS [ 38 ]. In addition, nephrin interacts with CD2AP with a subunit of PI3K and subsequently activates the Akt kinase pathway, which is necessary for regulating the actin cytoskeleton [ 39 ].…”

Case Report: The Monogenic Familial Steroid-Resistant Nephrotic Syndrome Caused by a Novel Missense Mutation of NPHS2 Gene A593C in a Chinese Family

“…The mutation of NPHS2 has been reported to occur in 13% of patients that manifested with SRNS before 25 years of age and accounted for the 34% of all 27 common genes in podocytes causing SRNS (10). To date, many novel NPHS2 gene mutations have been discovered and more genotype-phenotype correlations have been published, such as deletion c.988_989delCT, c.725C>T, c622G>A and c.928G>A et al (11)(12)(13). With the advent of the latest next gene screening technology and the development of molecular genome database platforms, more and more pathogenic genetic mutations contributing to pediatric SRNS have been identified in recent years (14)(15)(16).…”