Nephrotic Syndrome, Type 18

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 18 (NPHS18) is caused by homozygous or compound heterozygous mutation in the NUP133 gene (607613) on chromosome 1q42.

Biallelic mutation in the NUP133 gene can also cause Galloway-Mowat syndrome (GAMOS8; 618349).

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

Clinical Features

Braun et al. (2018) reported 3 patients from 2 unrelated families (A2174 and F797) with onset of nephrotic syndrome between 4 and 10 years of age. Renal biopsy of 2 patients showed focal segmental glomerulosclerosis and effacement of podocyte foot processes. All reached end-stage renal disease between 6 and 20 years of age. None had extrarenal manifestations. Family A2174 was nonconsanguineous and of Turkish origin; family F797 was consanguineous and of European origin.

Inheritance

The transmission pattern of NPHS18 in the families reported by Braun et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with NPHS18, Braun et al. (2018) identified homozygous or compound heterozygous missense mutations in the NUP133 gene (607613.0001-607613.0003). The mutations, which were found by exome sequencing or targeted exon sequencing and confirmed by Sanger sequencing, were shown to segregate with the disorder in the 1 family with available DNA. The mutations were unable to rescue abnormal kidney morphology in nup133-null Xenopus embryos, consistent with a loss of function. CRISPR/Cas9-mediated knockout of NUP133 in human podocytes increased the formation of filopodia and was associated with increased CDC42 (116952) activity, suggesting alteration of actin and cytoskeletal dynamics. The patients were part of a large study in which various nucleopore (NUP) genes were found to be mutated in NPHS, suggesting a common pathogenic pathway.