Focal Segmental Glomerulosclerosis 3, Susceptibility To

A number sign (#) is used with this entry because susceptibility to this form of hereditary renal disease, referred to here as focal segmental glomerulosclerosis-3 (FSGS3), is conferred by haploinsufficiency for CD2-associated protein (CD2AP; 604241) on chromosome 6p12.

Description

Focal segmental glomerulosclerosis (FSGS) is a pathologic entity associated clinically with proteinuria, the nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (Meyrier, 2005).

For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278).

Clinical Features

Lowik et al. (2007) reported a boy with severe early-onset nephrotic syndrome associated with FSGS who was born of consanguineous parents of Mediterranean ancestry. At age 10 months, he showed failure to thrive, proteinuria, microscopic hematuria, and anemia. Renal biopsy showed focal segmental glomerulosclerosis with mesangial matrix expansion and mild effacement of the podocyte processes. The disease progressed, and he had successful renal transplant at age 5 years.

Molecular Genetics

Kim et al. (2003) found that mice with haploinsufficiency for CD2AP exhibit a phenotype similar to human FSGS. They screened a study population of 30 African Americans with idiopathic FSGS as well as 15 African Americans with HIV-associated FSGS. As a normal control group, they selected 45 African Americans who had had HIV infection for at least 8 years with normal kidney function. Kim et al. (2003) detected 6 distinct DNA variants in 10 of 45 patients that were not present in any of the control subjects. One nucleotide variant, detected in 2 patients with primary FSGS, was predicted to alter the expression of CD2AP. This 2-bp substitution altered the exon 7 splice acceptor site (604241.0001).

In a boy with nephrotic syndrome associated with focal segmental glomerulosclerosis, Lowik et al. (2007) identified a homozygous mutation in the CD2AP gene (R612X; 604241.0002). There was no expression of the mutant protein in patient lymphocytes, consistent with a complete loss of function. Each unaffected parent was heterozygous for the mutation, indicating that heterozygosity for this mutation does not result in renal disease.

Nomenclature

In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature.