Gupta 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 ... Gupta 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.
In 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 ... In 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.