TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways

Am J Hum Genet. 2019 Feb 7;104(2):348-355. doi: 10.1016/j.ajhg.2018.12.016. Epub 2019 Jan 17.

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is characterized by high-range proteinuria and most often focal and segmental glomerulosclerosis (FSGS). Identification of mutations in genes causing SRNS has improved our understanding of disease mechanisms and highlighted defects in the podocyte, a highly specialized glomerular epithelial cell, as major factors in disease pathogenesis. By exome sequencing, we identified missense mutations in TBC1D8B in two families with an X-linked early-onset SRNS with FSGS. TBC1D8B is an uncharacterized Rab-GTPase-activating protein likely involved in endocytic and recycling pathways. Immunofluorescence studies revealed TBC1D8B presence in human glomeruli, and affected individual podocytes displayed architectural changes associated with migration defects commonly found in FSGS. In zebrafish we demonstrated that both knockdown and knockout of the unique TBC1D8B ortholog-induced proteinuria and that this phenotype was rescued by human TBC1D8B mRNA injection, but not by either of the two mutated mRNAs. We also showed an interaction between TBC1D8B and Rab11b, a key protein in vesicular recycling in cells. Interestingly, both internalization and recycling processes were dramatically decreased in affected individuals' podocytes and fibroblasts, confirming the crucial role of TBC1D8B in the cellular recycling processes, probably as a Rab11b GTPase-activating protein. Altogether, these results confirmed that pathogenic variations in TBC1D8B are involved in X-linked podocytopathy and points to alterations in recycling processes as a mechanism of SRNS.

Keywords: child; endocytosis; genetic; inherited; nephrotic syndrome; podocyte; rab11; recycling; trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Genetic Diseases, X-Linked / genetics*
  • Humans
  • Kidney Glomerulus / metabolism
  • Loss of Function Mutation*
  • Male
  • Nephrotic Syndrome / genetics*
  • Podocytes / cytology
  • Podocytes / metabolism
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism
  • Whole Exome Sequencing
  • Zebrafish
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism
  • rab GTP-Binding Proteins / metabolism

Substances

  • Calcium-Binding Proteins
  • TBC1D8B protein, human
  • Vesicular Transport Proteins
  • Zebrafish Proteins
  • tbc1d8b protein, zebrafish
  • rab11 protein
  • rab GTP-Binding Proteins