Gene

Kidney

Nephron

Slit diaphragm

Cell biology

Organoid

Induced pluripotent stem cell

Neuroscience

Biology

Kidney disease

Missense mutation

Endocrinology

Mutation

Cancer research

Acoustics

Loudspeaker

Genetics

Diaphragm (acoustics)

Physics

Podocyte

Nephrin

Embryonic stem cell

Proteinuria

Mutant

Glomerulonephritis

Focal segmental glomerulosclerosis

Internal medicine

Slit

Medicine

Nephrotic syndrome

Stem Cell Reports

Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. However, methods for SD reconstitution have been unavailable, thereby limiting studies in the field. In the present study, we established human induced pluripotent stem cells (iPSCs) from a patient with an NPHS1 missense mutation, and reproduced the SD formation process using iPSC-derived kidney organoids. The mutant NEPHRIN failed to become localized on the cell surface for pre-SD domain formation in the induced podocytes. Upon transplantation, the mutant podocytes developed foot processes, but exhibited impaired SD formation. Genetic correction of the single amino acid mutation restored NEPHRIN localization and phosphorylation, colocalization of other SD-associated proteins, and SD formation. Thus, these kidney organoids from patient-derived iPSCs identified SD abnormalities in the podocytes at the initial phase of congenital nephrotic disease.

Organoids from Nephrotic Disease-Derived iPSCs Identify Impaired NEPHRIN Localization and Slit Diaphragm Formation in Kidney Podocytes