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Abstract: FR-PO326

Phenotypic Quantification of Nphs1 Deficient Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mansour, Bshara, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kolvenbach, Caroline Maria, Boston Children's Hospital, Boston, Massachusetts, United States
  • Bao, Aaron, Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

The majority of children with steroid resistant nephrotic syndrome (SRNS) progress to end-stage renal disease (ESRD). Monogenic causes of SRNS have been detected in ~30% of pediatric cases, in one of 68 genes discovered so far, the most common being NPHS1 and NPHS2 (Kopp Nat Rev Dis Primers 6:68, 2020) affecting signaling pathways of podocytes biology (Connaughton NDT 35:390, 2020). Since each of these genes represents a rare cause of SRNS, tailoring therapeutic interventions to multiple molecular targets is challenging, and current treatments are limited. Therefore, gene replacement therapy (GRT) approaches have recently been considered (Zhao JCI Insight 22:e145936, 2021). To set the ground for GRT studies in-vivo, we established exact phenotypic quantification of a published Nphs1 knockout (ko) mouse model.


We have acquired a floxed nephrin mouse model (Nphs1tm1Afrn/J) that was previously studied for pathways linked to pancreatic β-cell survival (Villarreal J Am Soc Neprol 27:1029, 2016). We bred Nphs1fl/fl mice with a CRE recombinase expressing mouse under the control of podocin promoter [Tg(NPHS2-cre)295Lbh/J] (Moeller Genesis 35:39, 2003), to generate podocyte specific nephrin deficient mice. We then performed survival analysis, renal light microscopic (LM) and TEM analyses, and proteinuria assesment to quantitately phenotype these mice.


Mice were born in Mendelian ratios. We observed median survival of 5 days in Nphs1-/- mice (n=27) as compared to 100% survival in Nphs1-/+ (n=20) and Nphs1+/+ mice (n=13) until age 50 days. Quantification by LM of the ratio of proteinaceous casts in proximal tubules to number of glomeruli in the same sequential coronal kidney sections revealed a ratio of 0.92 casts/glomeruli (545/592) in Nphs1-/- mice (n=3), and 0/443 in Nphs1+/- controls (n=2). We counted the number of foot process cross sections (FPCS) per µm glomerular basement membrane (GBM) length in electron microscopy images. While Nphs1+/- mice (n=3) showed an avarage of 2.9 FPCS per µm of GBM, ko mice (n=3) showed 0.9 /1 µm GBM (p<0.05). Finally, Nphs1-/- pups had +4 albumin on urine stick (n=2), and Nphs1-/+ mice had trace to +1 readings (n=4).


We have quantitatively phenotyped Nphs1-/- mice, in a model that can provide reliable phenotypic read-outs for gene-replacement therapy in Nphs1 deficient mice.


  • NIDDK Support