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Kidney Week

Abstract: FR-PO792

Nephrin Mutation in Childhood-Adult Onset Nephrotic Syndrome (NS)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Saha, Manish K., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Henderson, Candace Dione, UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Gibson, Keisha L., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Ciavatta, Dominic J., University of North Carolina, Chapel Hill, North Carolina, United States
  • Derebail, Vimal K., University of North Carolina, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., UNC Kidney Center, Chapel Hill, North Carolina, United States

Nephrin, a slit diaphragm protein, is essential to integrity of podocyte structure. Mutations in the nephrin gene, NPHS1, typically result in congenital NS. Variants causing similar disease in later childhood and adults are rare. We believe our family is the first case report in which all members of the family have this mutation.
A 18-year-old Caucasian female was referred for steroid and calcineurin inhibitor resistant NS. Her first renal biopsy was at age 7 due to proteinuria with normal renal function and blood pressure. All 18 sampled glomeruli and interstitium appeared normal by light microscopy (LM), but electron microscopy (EM) showed partial foot process effacement. Repeat biopsy at age 18 when eGFR < 30 ml/min/1.73m2 showed focal segmental glomerulosclerosis, not otherwise specified (FSGS-NOS). She received Rituximab as attempted salvage therapy. Renal function deteriorated further and she reached end-stage disease by age 19. Her brother, at age 16, was evaluated and had nephrotic range proteinuria with preserved renal function. His renal biopsy showed 37 normal glomeruli by LM, with global activation of foot processes and effacement by EM. With consent, both patients and their parents (without proteinuria) were tested for a podocyte mutation


Genomic DNA was extracted from peripheral blood cells and genotyped for coding sequence variants in the NPHS1 gene in 9 healthy controls and the current family.


No homozygous variants in NPHS1 were detected in 9 healthy controls. The 2 children were homozygous for a pathogenic variant in NPHS1 c.2928G>T [p.Arg976Ser]. Both parents were heterozygous for this variant, representing a possible carrier-state. This mutation, a missense single nucleotide variation in exon 22, may affect mRNA splicing in the fibronectin domain of nephrin


We report two cases of childhood-onset proteinuria due to a NPHS1 missense mutation, with autosomal recessive inheritance. Renal pathology probably begins as a podocytopathy that slowly progresses to segmental glomerular sclerosis and renal impairment. NS due to genetic mutations may be resistant to conventional immunosuppressive therapy. Genetic testing may direct limitation of immunosuppression with minimal therapeutic benefit and inform counseling to future progeny