Focal Segmental Glomerulosclerosis 7

A number sign (#) is used with this entry because of evidence that focal segmental glomerulosclerosis-7 (FSGS7) is caused by heterozygous mutation in the PAX2 gene (167409) on chromosome 10q24.

Mutation in the PAX2 gene can also cause papillorenal syndrome (PAPRS; 120330), a more severe disorder with some overlapping features.

Description

Focal segmental glomerulosclerosis is a form of kidney injury defined by partial sclerosis of some but not all glomeruli. It is characterized clinically by significant proteinuria with or without features of nephrotic syndrome. Some patients develop end-stage renal disease (summary by Barua et al., 2014).

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

Clinical Features

Barua et al. (2014) reported 24 patients from 7 unrelated families with focal segmental glomerulosclerosis. FSGS was defined as having a history of proteinuria, nephrotic syndrome, or biopsy-proven FSGS. The age at onset ranged from 8 to 68 years, but most patients had onset in the second to fourth decades. No ocular or auditory abnormalities were documented. Nine patients developed end-stage renal disease. Ultrasound performed in some patients showed variable subtle abnormalities, including increased echogenicity, dilated renal pelvis, small kidneys, and calyceal diverticulum. Renal biopsy of 1 patient was described in detail: in addition to FSGS, electron microscopy showed diffuse podocytopathy with degenerative changes and focal foot process effacement. Reevaluation of 1 of the families revealed a more severe phenotype, compatible with undiagnosed papillorenal syndrome; this family carried a nonsense mutation. The findings expanded the phenotypic spectrum associated with PAX2 mutations.

Inheritance

The transmission pattern of FSGS7 in the families reported by Barua et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In affected members of 7 unrelated families with FSGS, Barua et al. (2014) identified 7 different heterozygous mutations in the PAX2 gene (see, e.g., 167409.0013 and 167409.0014). Six families carried a missense mutation, and 1 with a more severe phenotype carried a nonsense mutation. The mutation in the first family was found by whole-exome sequencing, and the subsequent mutations were found by sequencing this gene in a cohort of 175 patients with familial disease. PAX2 mutations were found in 4% of the total cohort. In vitro functional expression studies of some of the mutations showed that some perturbed protein function by affecting proper binding to DNA causing reduced transactivation activity or by enhancing the repressor activity of PAX2. The findings indicated that PAX2 mutations can cause disease through haploinsufficiency or a dominant-negative effect.