PUBLICATION

A zebrafish model of congenital nephrotic syndrome of the Finnish type

Authors
Lee, M.S., Devi, S., He, J.C., Zhou, W.
ID
ZDB-PUB-221004-9
Date
2022
Source
Frontiers in cell and developmental biology   10: 976043 (Journal)
Registered Authors
Zhou, Weibin
Keywords
CRISPR/Cas9, NPHS1, hypoalbuminemia, nephrin, nephrotic syndrome, zebrafish
MeSH Terms
none
PubMed
36187478 Full text @ Front Cell Dev Biol
Abstract
Nephrotic syndrome (NS) is a disease characterized by proteinuria and subsequent hypoalbuminemia, hyperlipidemia and edema due to the defective renal glomerular filtration barrier (GFB). Mutations of NPHS1, encoding NEPHRIN, a podocyte protein essential for normal GFB, cause congenital nephrotic syndrome (CNS) of the Finnish type (CNF), which accounts for about 50% of CNS cases. We generated zebrafish nphs1 mutants by using CRISPR/Cas9. These mutants completely lack nephrin proteins in podocytes and develop progressive peri-orbital and whole-body edema after 5 days post fertilization. Ultra-structurally, loss of nephrin results in absence of slit-diaphragms and progressive foot process effacement in zebrafish pronephric glomeruli, similar to the pathological changes in human CNF patients. Interestingly, some nphs1 mutants are viable to adulthood despite ultra-structural defects in renal glomeruli. Using a reporter line Tg (l-fabp:VDBP-GFP) expressing GFP-tagged vitamin-D-binding protein in the blood plasma, we observed a reduction of intravascular GFP fluorescence in the nphs1 mutants, a hypoalbuminemia-like phenotype. In addition, we detected excretion of GFP by the nphs1 mutants, reminiscent of proteinuria. Therefore, we have demonstrated that the nphs1 mutant zebrafish recapitulate the human NS phenotypes and provide a novel and relevant animal model useful for screening therapeutical agents for this disease.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
nphs1mss102/mss102 (AB)standard conditionsDay 5
nphs1mss102/mss102 (AB)standard conditionsDay 5
nphs1mss102/mss102 (AB)standard conditionsDay 5
nphs1mss102/mss102 (AB)standard conditionsDay 6
nphs1mss102/mss102 (AB)standard conditionsDay 6
nphs1mss102/mss102 (AB)standard conditionsDays 7-13
nphs1mss102/mss102 (AB)standard conditionsDays 7-13
nphs1mss102/mss102 (AB)standard conditionsDays 7-13
nphs1mss102/mss102 (AB)standard conditionsDays 7-13
nphs1mss102/mss102 (AB)standard conditionsDays 7-13
1 - 10 of 36
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mi1000TgTransgenic Insertion
    mss102
      		Small Deletion
      mss103
        		Small Deletion
        zf238TgTransgenic Insertion
          1 - 4 of 4
          Show
          Human Disease / Model
          Human Disease Fish Conditions Evidence
          nephrotic syndrome type 1nphs1mss102/mss102 (AB)standard conditionsTAS
          nephrotic syndrome type 1nphs1mss103/mss103 (AB)standard conditionsTAS
          1 - 2 of 2
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          Sequence Targeting Reagents
          Target Reagent Reagent Type
          nphs1CRISPR3-nphs1CRISPR
          1 - 1 of 1
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          Fish
          Fish
          AB
          mi1000Tg
          nphs1mss102/mss102 (AB)
          nphs1mss102/mss102; mi1000Tg
          nphs1mss102/mss102; zf238Tg
          nphs1mss102/+ (AB)
          nphs1mss102/+; zf238Tg
          nphs1mss103/mss103 (AB)
          nphs1mss103/mss103; mi1000Tg
          nphs1mss103/mss103; zf238Tg
          1 - 10 of 13
          Show
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab3-nphs1polyclonalRabbit
          Ab4-nphs2polyclonal
            		IgGRabbit
            1 - 2 of 2
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            Orthology
            No data available
            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            1 - 1 of 1
            Show
            Mapping
            No data available
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            Citation
            Lee, M.S., Devi, S., He, J.C., Zhou, W. (2022) A zebrafish model of congenital nephrotic syndrome of the Finnish type. Frontiers in cell and developmental biology. 10:976043.