Nephrotic Syndrome, Type 16

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 16 (NPHS16) is caused by homozygous mutation in the KANK2 gene (614610) on chromosome 19p13.

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

Clinical Features

Gee et al. (2015) reported 3 children from 2 unrelated families with onset of nephrotic syndrome between 2 and 3 years of age. Two sibs, born of consanguineous Arab parents (family A982), had steroid-sensitive nephrotic syndrome, whereas the unrelated patient of European descent (family A1751) had steroid-dependent nephrotic syndrome and hematuria. Renal biopsy of all 3 patients showed minimal change disease. Additional clinical details were not provided, but none had extrarenal manifestations.

Inheritance

The transmission pattern of NPHS16 in the families reported by Gee et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with NPHS16, Gee et al. (2015) identified homozygous missense mutations in the KANK2 gene (S181G, 614610.0002 and S684F, 614610.0003). The mutation in 2 affected sibs in a consanguineous family of Arab descent (family A982) was found by a combination of homozygosity mapping and whole-exome sequencing. The mutation in the unrelated patient (patient A1751-21) was found by direct sequencing of the KANK2 gene in over 1,100 patients with nephrotic syndrome; this was the only patient found to have a KANK2 mutation in that cohort. Injection of either mutation failed to rescue the nephrotic syndrome phenotype in zebrafish with morpholino knockdown of the kank2 gene, suggesting that the mutations result in a loss of function. Wildtype KANK2 was able to partially rescue the edema phenotype in mutant zebrafish. In vitro functional assays suggested that the mutations resulted in dysregulation of RHO GTPase activity and signaling.

Animal Model

Gee et al. (2015) found that morpholino knockdown of the Kank2 gene in zebrafish embryos resulted in increased frequency of periorbital edema and total body edema associated with proteinuria. Pronephric glomeruli in mutant animals showed podocyte foot effacement and disorganization, rarefaction of slit membranes, and disorganization of the glomerular basement membrane, consistent with a nephrosis phenotype. The findings suggested that kank2 is required for normal cytoskeletal structure.