Focal Segmental Glomerulosclerosis 8

A number sign (#) is used with this entry because focal segmental glomerulosclerosis-8 (FSGS8) is caused by heterozygous mutation in the ANLN gene (616027) on chromosome 7p14.

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

Clinical Features

Gbadegesin et al. (2014) reported 2 unrelated families with proteinuria due to focal segmental glomerulosclerosis confirmed by renal biopsy. Some clinical details of 1 large 4-generation family were provided. The age at onset varied greatly, between 9 and 69 years, and end-stage renal disease occurred between 35 and 75 years. Five patients underwent renal transplant with no recurrence in the renal allograft.

Inheritance

The transmission pattern of FSGS8 in the families reported by Gbadegesin et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a large 4-generation family with autosomal dominant FSGS8, Gbadegesin et al. (2014) identified a heterozygous missense mutation in the ANLN gene (R431C; 616027.0001). The mutation was found by a combination of linkage analysis and whole-exome sequencing focusing on genes known to be enriched in the podocyte. Mutational screening of the ANLN gene in 250 families with FSGS identified 1 missense mutation (G618C; 616027.0002) that segregated with the disorder in 1 family. Overexpression of the R431C mutant in HEK293 cells resulted in reduced and defective binding to CD2AP (604241) compared to wildtype, and cells carrying the mutation showed increased cell motility compared to wildtype in a wound-healing assay. The findings suggested that anillin may play a significant role in podocyte cell migration. Renal biopsy specimens from humans with idiopathic FSGS showed increased expression of anillin in the glomerulus, whereas synaptopodin (SYNPO; 608155) expression was downregulated. Gbadegesin et al. (2014) postulated that differentiated podocytes that express anillin are likely to be abnormal, since anillin is usually expressed in actively dividing cells.

Animal Model

Gbadegesin et al. (2014) found that morpholino-mediated knockdown of anillin in zebrafish caused severe edema. Transmission electron microscopy revealed fusion and almost complete effacement of podocyte foot processes as well as disorganization of the glomerular filtration barrier.