2. Academic Validation
  3. TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways

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.
Guillaume Dorval 1,  Valeryia Kuzmuk 2,  Olivier Gribouval 1,  Gavin I Welsh 2,  Agnieszka Bierzynska 2,  Alain Schmitt 3,  Stéphanie Miserey-Lenkei 4,  Ania Koziell 5,  Shuman Haq 6,  Alexandre Benmerah 1,  Géraldine Mollet 1,  Olivia Boyer 7,  Moin A Saleem 8,  Corinne Antignac 9
Affiliations

Affiliations

  • 1 Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, 75015 Paris, France.
  • 2 Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, UK.
  • 3 Inserm, U1016, Institut Cochin, 75014 Paris, France; Cnrs, UMR8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
  • 4 Institut Curie, PSL Research University, CNRS, UMR 144, Molecular Mechanisms of Intracellular Transport, 75005 Paris, France.
  • 5 Department of Children's Nephrology and Urology, Evelina London, London SE1 7EH, UK.
  • 6 Paediatric Nephrology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.
  • 7 Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, 75015 Paris, France; Department of Pediatric Nephrology, Reference center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP, 75015 Paris, France.
  • 8 Bristol Renal, University of Bristol and Bristol Royal Hospital for Children, Bristol, UK. Electronic address: m.saleem@bristol.ac.uk.
  • 9 Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, 75015 Paris, France; Department of Genetics, Reference center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP,75015 Paris, France. Electronic address: corinne.antignac@inserm.fr.
PMID: 30661770 DOI: 10.1016/j.ajhg.2018.12.016
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.

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