Focal Segmental Glomerulosclerosis 5

A number sign (#) is used with this entry because this form of hereditary renal disease, referred to here as focal segmental glomerulosclerosis-5 (FSGS5), is caused by heterozygous mutation in the INF2 gene (610982) on chromosome 14q32.33.

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).

Dominant intermediate Charcot-Marie-Tooth disease E and focal segmental glomerulonephritis (CMTDIE; 614455) is also caused by heterozygous mutation in the INF2 gene.

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

Clinical Features

Brown et al. (2010) studied 11 families with focal segmental glomerulosclerosis in which affected individuals displayed shared features, including onset of disease in adolescence or adulthood and proteinuria that was typically moderate. Microscopic hematuria and hypertension were seen in some individuals, and many had proteinuria in the nephrotic range, but none had other manifestations of the clinical nephrotic syndrome (see 256300) such as hypoalbuminemia or edema. The disease and the proteinuria were progressive, often leading to end-stage renal disease. Renal biopsies showed the presence of FSGS on light microscopy, and electron microscopy showed focal areas of podocyte foot-process effacement, typical of secondary and some genetic forms of FSGS, as well as areas where foot processes and slit-diaphragms were well preserved. Brown et al. (2010) also observed unusually prominent actin bundles within the foot processes. Noting that glomerular hypertrophy was not a prominent feature of the biopsies, and that there were no perihilar collapsing or cellular lesions, they stated that these biopsies would be characterized as 'FSGS, not otherwise specified' in the classification scheme of D'Agati et al. (2004).

Mapping

In a large family segregating autosomal dominant FSGS, Brown et al. (2010) performed genotyping with SNP markers followed by focused microsatellite genotyping in 22 family members and obtained a maximum 2-point lod score of 4.00 (theta = 0.05) at D14uc23CA104 on chromosome 14q32. In another large FSGS family with a similar clinical course, Brown et al. (2010) stated that they had previously performed linkage analysis and obtained a maximum 2-point lod score of 3.69 near the telomere of chromosome 14q, at D14S1426. Under the assumption that FSGS in both families was caused by a defect in the same gene, a critical region was defined between rs3783397 and rs6576201.

Inheritance

The pedigree pattern in 2 families with focal segmental glomerulosclerosis was consistent with autosomal dominant inheritance (Brown et al., 2010).

Molecular Genetics

In 2 large families segregating autosomal dominant FSGS mapping to chromosome 14q32, Brown et al. (2010) sequenced 15 candidate genes and identified heterozygous missense mutations in the INF2 gene (610982) that segregated with disease (610982.0001 and 610982.0002) in both families. Sequencing of the INF2 gene in 91 unrelated individuals with familial FSGS identified 9 additional families with heterozygous mutations in the INF2 gene (see, e.g., 610982.0003-610982.0005).

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.