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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)348-355
Number of pages8
JournalAmerican Journal of Human Genetics
Volume104
Issue number2
Early online date17 Jan 2019
DOIs
DateAccepted/In press - 20 Dec 2018
DateE-pub ahead of print - 17 Jan 2019
DatePublished (current) - 7 Feb 2019

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.

    Research areas

  • podocyte, nephrotic syndrome, endocytosis, recycling, inherited, rab11, child trafficking, genetic

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier (Cell Press) at https://www.sciencedirect.com/science/article/pii/S0002929718304695 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 864 KB, PDF document

    Embargo ends: 17/01/20

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    Licence: CC BY-NC-ND

  • Supplementary Figures

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier (Cell Press) at https://www.sciencedirect.com/science/article/pii/S0002929718304695 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1 MB, PDF document

    Embargo ends: 17/01/20

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    Licence: CC BY-NC-ND

DOI

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