Focal Segmental Glomerulosclerosis 9

A number sign (#) is used with this entry because of evidence that focal segmental glomerulosclerosis-9 (FSGS9) is caused by homozygous or compound heterozygous mutation in the CRB2 gene (609720) on chromosome 9q33.

Biallelic mutation in the CRB2 gene can also cause ventriculomegaly with cystic kidney disease (VMCKD; 219730), a much more severe disorder.

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

Clinical Features

Ebarasi et al. (2015) reported 5 patients from 4 families with onset of steroid-resistant nephrotic syndrome between 9 months and 6 years of age. Renal biopsy, available in 4 patients, showed focal segmental glomerulosclerosis. Two of the families were consanguineous and of Turkish origin. There were no additional systemic features.

Inheritance

The transmission pattern of FSGS9 in the families reported by Ebarasi et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 families with childhood-onset FSGS9, Ebarasi et al. (2015) identified homozygous or compound heterozygous mutations in the CRB2 gene (609720.0001-609720.0005). Mutations in the first 2 families were found by homozygosity mapping and/or whole-exome sequencing; mutations in the second 2 families were found by sequencing the CRB2 gene in 1,010 families with steroid-resistant nephrotic syndrome. Three of the mutations occurred at highly conserved residues in the tenth EGF-like domain; complementation studies in crb2-null zebrafish demonstrated that 2 of these mutations resulted in loss of protein function. Overall, the findings implicated defects in podocyte apicobasal polarity in the pathogenesis of FSGS9.

Animal Model

Ebarasi et al. (2015) found that zebrafish homozygous for a crb2-null mutation developed pronephric cysts and pericardial edema, indicating kidney dysfunction. Homozygous null animals also had smaller eyes, consistent with a requirement for crb2 in photoreceptor differentiation. Histologic examination showed defects in glomerular morphogenesis, and electron microscopy showed disruption of podocyte foot processes and lack of basement membrane fenestrations in capillary endothelial cells. In addition, foot processes contained vesicular-like structures and apical membrane projections. These findings suggested that crb2 is required for correct foot process arborization and podocyte morphologic differentiation. The apical membrane of crb2-null podocytes showed ectopic projections into the Bowman space, and several membrane proteins were mislocalized, suggesting defects in apical membrane differentiation and protein trafficking, consistent with a polarity defect.