Focal Segmental Glomerulosclerosis 2

A number sign (#) is used with this entry because of evidence that this form of hereditary renal disease, termed focal segmental glomerulosclerosis-2 (FSGS2), is caused by mutation in the TRPC6 gene (603652) on chromosome 11q22.

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) (review by Meyrier, 2005).

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

Clinical Features

Winn et al. (1999, 1999) reported a 399-member Caucasian kindred of British heritage dating back 7 generations from the south of New Zealand in which 14 deceased individuals had had ESRD, 14 living family members were on dialysis or had undergone renal transplantation, and 3 individuals were found to have proteinuria greater than 3+ by qualitative urinalysis.

Mapping

In a 399-member Caucasian kindred of British heritage with hereditary renal disease, Winn et al. (1999, 1999) found linkage to chromosome 11q21-q22, with a maximum lod score of 9.89.

Genetic Heterogeneity

In a 5-generation, 65-member Caucasian kindred from rural eastern North Carolina, Winn et al. (1999) excluded linkage to chromosome 11 and to the previously described locus on 19q13 (FSGS1). There were no shared haplotypes among affected individuals in 3 smaller families. The findings demonstrated genetic heterogeneity in FSGS, with at least 3 genes causing this phenotype.

Molecular Genetics

In affected members of the British family segregating FSGS linked to chromosome 11q21-q22 identified by Winn et al. (1999), Winn et al. (2005) identified a mutation in exon 2 of the TRPC2 gene that caused a missense change in the first ankyrin repeat of the protein (P112Q; 603652.0001).

Reiser et al. (2005) identified 5 families with autosomal dominant focal segmental glomerulosclerosis in which the disease segregated with mutations in the TRPC6 gene on 11q. Two of the TRPC6 mutants had increased current amplitudes. The authors demonstrated that TRPC6 is expressed in podocytes and is a component of the glomerular slit diaphragm. These data showed that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

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.