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In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation
- Source :
- Kidney International. 66:945-954
- Publication Year :
- 2004
- Publisher :
- Elsevier BV, 2004.
-
Abstract
- In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. Background Mutations in NPHS2, encoding podocin, are a prevalent cause of autosomal-recessive steroid-resistant nephrotic syndrome (SRNS). Podocin is a protein associated with the slit diaphragm that interacts with nephrin and CD2-associated protein (CD2AP) within lipid rafts. Methods Using renal biopsies of six patients, we analyzed the in vivo consequences of different types of NPHS2 mutations on ( 1 ) the podocyte expression and distribution of podocin using in situ hybridization and immunohistology and ( 2 ) the distribution of related podocyte proteins and glomerular extracellular matrix components. Results In two patients with homozygous 855_856delAA or 419delG mutation, absence of podocyte labeling with the antibodies against the C-terminal domain contrasted with the normal expression of the N-terminal domain of the protein along the glomerular basement membrane (GBM). In patients carrying compound heterozygous mutations or variants (R168S/467_468insT, R138Q/V180M, and R291W/R229Q), or single heterozygous 976_977insA, podocin transcription appeared unchanged but the distribution of the protein was modified. Podocin was restricted to the podocyte body in the patient carrying the R168S/467_468insT mutation whereas strong immunolabeling of the podocyte body was associated with discrete labeling along the GBM in the three others. In all cases, podocin defect was associated with changes in the distribution of nephrin, CD2AP, and α-actinin: the proteins were mainly detected in the podocyte body, with mild expression along the GBM. There were no detectable changes in the distribution of other podocyte proteins or glomerular extracellular matrix components. Conclusion NPHS2 mutations result in profound alteration of podocin expression and/or distribution. Secondary changes in the distribution of nephrin, CD2AP, and α-actinin are additional evidences for the scaffolding role of podocin in the organization of the slit diaphragm.
- Subjects :
- Male
medicine.medical_specialty
Nephrotic Syndrome
NPHS2
Adolescent
Kidney Glomerulus
Fluorescent Antibody Technique
Gene Expression
CD2AP
In situ hybridization
Biology
urologic and male genital diseases
Podocyte
Nephrin
Internal medicine
steroid-resistant nephrotic syndrome
medicine
Humans
Point Mutation
Actinin
Child
Adaptor Proteins, Signal Transducing
Extracellular Matrix Proteins
urogenital system
Glomerular basement membrane
Homozygote
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Proteins
Glomerulonephritis
nephrin
medicine.disease
Molecular biology
female genital diseases and pregnancy complications
Cytoskeletal Proteins
α-actinin
Endocrinology
medicine.anatomical_structure
Nephrology
Child, Preschool
Slit diaphragm
biology.protein
Podocin
Female
Nephrotic syndrome
podocin
Subjects
Details
- ISSN :
- 00852538
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Kidney International
- Accession number :
- edsair.doi.dedup.....9665f3fe078212de322f98d83013bb5e