Nephrotic Syndrome, Type 20

A number sign (#) is used with this entry because of evidence that nephrotic syndrome type 20 (NPHS20) is caused by hemizygous or heterozygous mutation in the TBC1D8B gene (301027) on chromosome Xq22.

Description

Nephrotic syndrome type 20 (NPHS20) is an X-linked renal disorder characterized by onset of steroid-resistant nephrotic syndrome and proteinuria in the first years of life in affected males. The disorder results in end-stage kidney disease and may cause death in childhood without renal transplantation. Carrier females may have a milder disorder with proteinuria or may be unaffected. Renal biopsy typically shows focal segmental glomerulosclerosis (FSGS) and effacement of podocyte foot processes (summary by Dorval et al., 2019).

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

Clinical Features

Dorval et al. (2019) reported 3 brothers, born of unrelated parents from Ecuador (family A), with congenital onset of steroid-resistant nephrotic syndrome. Two of the affected brothers died in the first years of life; the remaining brother reached end-stage kidney disease at age 2.8 years and underwent successful renal transplantation with no disease recurrence. The boys' mother and sister, who carried the same mutation in the TBC1D8B gene that had been identified in the living brother, had later onset of proteinuria without frank nephrotic syndrome: as an adult in the mother and at age 7 in the sister. In addition, the pregnancies were complicated by preeclampsia when carrying a male fetus. Renal biopsy of the male proband and his sister showed focal segmental glomerulosclerosis (FSGS) and effacement of podocyte foot processes. An unrelated European boy with the disease presented with steroid-resistant nephrotic syndrome at 2 years of age. Renal biopsy showed glomerulosclerosis and effacement of foot processes. He reached end-stage renal disease at age 9 and underwent successful renal transplant.

Inheritance

The transmission pattern of NPHS20 in the families reported by Dorval et al. (2019) was consistent with X-linked inheritance. In 1 family, female mutation carriers were mildly affected, whereas in the other family, the female carrier was unaffected.

Molecular Genetics

In a boy from a family from Ecuador (family A) with NPHS20, Dorval et al. (2019) identified a hemizygous missense mutation in the TBC1D8B gene (Q246H; 301027.0001). The patient's mother and sister, who had milder symptoms, were heterozygous for the mutation. The proband had 2 affected brothers who were deceased; their DNA was not available for study. Subsequently, an unrelated boy of European descent (family B) was found to carry a different hemizygous TBC1D8B missense mutation (F291S; 301027.0002) inherited from his unaffected mother. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, affected highly conserved residues in the GRAM domains and segregated with the disorder in the families. Podocytes from the second boy showed abnormalities in actin cytoskeletal organization associated with changes in adhesion and migration. Functional studies of patient podocytes or fibroblasts showed a delay in endocytosis, consistent with defects in vesicular recycling. Patient cells also showed mislocalization of Rab11b (604198) compared to controls. Expression of the human mutations only partially rescued the renal phenotype of zebrafish with knockdown of the tbc1d8b gene, suggesting that the mutations retained some residual function.

Animal Model

Dorval et al. (2019) found that knockdown or knockout of tbc1d8b in zebrafish caused a glomerular filtration barrier defect and proteinuria. Histologic and electron microscopic examination showed a retracted glomerulus in an enlarged Bowman capsule and significant foot process effacement and disappearance of slit diaphragms in kidney of tbc1d8b -/- zebrafish. Wildtype human TBC1D8B short isoform significantly rescued the phenotype in tbc1d8b -/- zebrafish, whereas human TBC1D8B with mutations associated with steroid-resistant nephrotic syndrome only partially rescued the phenotype.