Nephrotic Syndrome, Type 12

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 12 (NPHS12) is caused by homozygous or compound heterozygous mutation in the NUP93 gene (614351) on chromosome 16q13.

Description

Nephrotic syndrome type 12 is an autosomal recessive renal disorder caused by defects in the renal glomerular filter. Affected individuals have onset of progressive renal failure in the first years of life. Renal biopsy typically shows focal segmental glomerulosclerosis (FSGS) (summary by Braun et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).

Clinical Features

Braun et al. (2016) reported 7 children from 6 unrelated families with steroid-resistant nephrotic syndrome. The age at onset ranged from 1 to 6 years and end-stage kidney disease became apparent between 1 and 11 years. Renal biopsy showed focal segmental glomerulosclerosis; diffuse mesangial sclerosis was apparent in 1 family. There was also evidence of a renal tubular phenotype involving proximal tubular dilation with protein casts and interstitial cell infiltrations. Electron microscopy showed partial podocyte foot process effacement. One patient showed partial response to steroids and 2 patients partially responded to cyclosporin A.

Inheritance

The transmission pattern of NPHS12 in the families reported by Braun et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 children from 6 unrelated families with NPHS12, Braun et al. (2016) identified homozygous or compound heterozygous mutations in the NUP93 gene (614351.0001-614351.0005). The mutations were found by homozygosity mapping and whole-exome sequencing in some families, and by high-throughput exon sequencing in other families. All mutations segregated with the disorder in the families. In vitro function expression studies showed that some, but not all, of the mutations disrupted assembly of the nuclear pore complex. Cellular knockdown of NUP93 disrupted BMP7 (112267)-dependent activation of SMAD (see, e.g., SMAD1; 601595) signaling, and none of the mutations was able to rescue the defect in BMP7-dependent SMAD signaling in knockdown human podocytes and HEK293 cells. Thus, all mutations resulted in a loss of NUP93 function, and all shared a defect in BMP7-dependent SMAD signaling and transcription, which may represent a novel pathogenic mechanism underlying NPHS.