Nephrotic Syndrome, Type 8
A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 8 (NPHS8) is caused by homozygous mutation in the ARHGDIA gene (601925) on chromosome 17q25.
For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Clinical FeaturesGupta et al. (2013) reported 2 sisters, born of consanguineous Pakistani parents, with congenital nephrotic syndrome. Both girls presented in the first weeks of life with severe proteinuria, hypoalbuminemia, and generalized edema. Renal biopsy of 1 patient showed diffuse mesangial sclerosis, with small glomeruli, hypercellularity, increased extracellular matrix, and contracted/collapsed glomerular tufts surrounded by immature or abnormal podocytes. Electron microscopy showed diffuse effacement of foot processes, thinning of the glomerular basement membrane, and swollen endothelial cells. One patient underwent renal transplant at age 2 years, but the graft never functioned due to venous thrombosis, and she remained on dialysis. The second child died at age 2 months without treatment.
Gee et al. (2013) reported 2 sibs, born of consanguineous Ashkenazi Jewish parents (family A1432), with early-onset steroid-resistant nephrotic syndrome. One child presented at age 2.4 years with end-stage renal disease and diffuse mesangial sclerosis on renal biopsy. The other sib presented at age 1 year with steroid-resistant nephrotic syndrome and developed end-stage renal disease by age 3. Both sibs had intellectual disability and one had sensorineural hearing loss. A third sib in this family reportedly developed nephrotic syndrome at age 1 and died at age 19 months, but no additional information was provided and no DNA was available for testing. Gee et al. (2013) also reported a Moroccan child, born of consanguineous parents, who presented at 14 days of age with nephrotic syndrome, which progressed to end-stage renal disease by age 6 weeks. This child had seizures and cortical blindness and died at age 6 months.
InheritanceThe transmission pattern of congenital nephrotic syndrome in the family reported by Gupta et al. (2013) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn 2 sisters, born of consanguineous Pakistani parents, with congenital nephrotic syndrome type 8, Gupta et al. (2013) identified a homozygous 3-bp in-frame deletion in the ARHGDIA gene (601925.0001). The mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and not found in multiple controls. In vitro functional studies and studies of patient fibroblasts showed that the mutation resulted in the hyperactivation of 3 Rho-GTPases due to loss of ARHGDIA function and caused impaired cell motility. The findings suggested that the mutation caused an imbalance in the active and inactive forms of Rho-GTPases, leading to derangements in the actin cytoskeleton within podocytes and subsequent nephrotic syndrome. Gupta et al. (2013) noted that Arhgdia-null mice also develop proteinuria and progressive renal failure.
By homozygosity mapping and exome sequencing in 2 sibs of Ashkenazi Jewish descent with early-onset steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis, Gee et al. (2013) identified a homozygous mutation in the ARHGDIA gene (G173V; 601925.0003). Screening of the ARHGDIA gene in 65 individuals with diffuse mesangial sclerosis and 350 individuals with steroid-resistant nephrotic syndrome identified a different homozygous mutation (R120X) in a Moroccan infant with congenital nephrotic syndrome. Both mutations were confirmed by Sanger sequencing and segregated with the disorder in the families. Gee et al. (2013) demonstrated that the mutations abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 (602048) and CDC42 (116952), resulting in a migratory phenotypic change of podocytes (foot process effacement) and proteinuria. Knockdown of arhgdia in zebrafish recapitulated the nephrotic phenotype, which was partially rescued with RAC1 inhibitors.
Animal ModelShibata et al. (2008) found that Arhgdia -/- mice developed progressive renal disease characterized by heavy albuminuria and podocyte damage.