CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS)

Nephrol Dial Transplant. 2009 Jun;24(6):1858-64. doi: 10.1093/ndt/gfn712. Epub 2009 Jan 7.


Background: CD2-associated protein (CD2AP) is a crucial protein for the slit-diaphragm assembly and function. In spite of the fact that CD2AP knockout causes nephrotic syndrome in mice and the heterozygous +/- mouse is prone to proteinuria, little is known about the relevance of this molecule in human renal pathology.

Methods: A total of 80 Italian patients with idiopathic nephrotic syndrome were enrolled and screened for changes in the CD2AP gene. A normal control group of 200 healthy donors was also studied. The coding region of the CD2AP gene was analysed by polymerase chain reaction, denaturing high-performance liquid chromatography and sequencing. Peripheral blood mononuclear cells from patients with CD2AP mutations and from healthy donors were isolated by the Ficoll-Hypaque gradient, and the CD2/CD2AP interaction was studied on T-lymphocytes by confocal laser scanning microscopy analysis. The expression levels of CD2AP, nephrin and podocin proteins were evaluated by indirect immunofluorescence on renal biopsies from a patient with p.delGlu525 mutation and from control subjects. Moreover, the effect of the p.K301M mutation on cell viability was evaluated by flow cytometry and annexin V/propidium iodide staining.

Results: Three heterozygous mutations (c.904A>T; c.1120A>G; c.1573delAGA) producing respectively aminoacidic changes (p.K301M, p.T374A) or a deletion in functional domains (p.delGlu525) were found in three unrelated patients. One (p.K301M) produced a lysine to methionine change in the third interactive SH3 domain (position 301) and resulted in the defective CD2-CD2AP interaction and clustering; the other (c.1573delAGA) caused the deletion of the glutamic acid in position 525 in the COOH-terminal region of binding with nephrin and was associated with down-modulation of CD2AP, podocin and nephrin glomerular expression.

Conclusions: Our findings suggest that CD2AP mutations modify the interaction with CD2 in lymphocytes and alter the composition of the renal slit diaphragm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Apoptosis
  • Base Sequence
  • CD2 Antigens / metabolism
  • Case-Control Studies
  • Child, Preschool
  • Cytoskeletal Proteins / deficiency
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • DNA / genetics
  • Female
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Glomerulosclerosis, Focal Segmental / pathology
  • Glomerulosclerosis, Focal Segmental / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / pathology
  • Nephrotic Syndrome / physiopathology
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • T-Lymphocytes / pathology
  • T-Lymphocytes / physiology
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • CD2 Antigens
  • CD2-associated protein
  • Cytoskeletal Proteins
  • DNA