Case Report: A Novel Heterozygous Mutation of CD2AP in a Chinese Family With Proteinuria Leads to Focal Segmental Glomerulosclerosis

Abstract

Idiopathic focal segmental glomerulosclerosis (FSGS) is a relatively frequent kidney disorder that manifest clinically as proteinuria and progressive loss of renal function. Genetic factors play a dominant role in the occurrence of FSGS. CD2-associated protein (CD2AP) is an adapter molecule and is essential for the slit-diaphragm assembly and function. Mutations in the CD2AP gene can contribute to FSGS development. Here, we describe a Chinese family of four generations with unexplained proteinuria. The proband, a 12-year-old boy, was diagnosed as FSGS. Whole-exome sequencing (WES) revealed an unknown frameshift insertion mutation (p.K579Efs^*7) of CD2AP gene that leads to a truncation of CD2AP protein. Bioinformatics strategies predicted that the novel mutation was pathogenic. The mutation was absent in either healthy family members or our 200 healthy controls. In summary, we used WES to explore the genetic lesion of FSGS patients and identified a novel mutation in CD2AP gene. This work broadens the mutation spectrum of CD2AP gene and provides data for genetic counseling to additional FSGS patients.

Keywords: CD2AP; FSGS; heterozygote; mutation; whole-exome sequencing.

Figure 1

The clinic and sequencing data of this FSGS family. (A) The pedigree of this FSGS family. Squares indicate male family members; circles, female members; black symbols, the affected members; white symbols, unaffected members; arrow, proband. (B) HE staining (C) Masson staining for renal biopsy of the proband (IV-1). (D) Sanger DNA sequencing chromatogram demonstrates a heterozygosity mutation (c.1734_1735insG/p.K579Efs*7) of CD2AP gene in affected members. (E) Alignment of multiple CD2AP protein sequences across species. Letters in red show the K579 site is evolutionarily conserved.

Figure 2

The bioinformatics analysis of mutations. (A) Structure prediction of the mutant protein. The wild type CD2AP (CD2AP-WT) protein structure and the p.K579Efs*7 mutant CD2AP (CD2AP-p.K579Efs*7) protein structure were predicted by SWISS-MODEL online software. (B) Overview of all known and novel CD2AP mutations. The CD2AP gene is shown, with all known CD2AP mutations (black letters) and novel mutation (red letters). Blue rectangles indicate exons. Introns are not shown to scale. The CD2AP protein structure is shown. CC, coiled-coil domain; SH3, Src homology 3 domain.