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

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TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. / Dorval, Guillaume; Kuzmuk, Valeryia; Gribouval, Olivier; Welsh, Gavin; Bierzynska, Agnieszka; Schmitt, Alain; Miserey-Lenkei, Stephanie; Koziell, Ania; Haq, Shuman; Benmerah, Alexandre; Mollet, Geraldine ; Boyer, Olivia; Saleem, Moin; Antignac, Corinne.

In: American Journal of Human Genetics, Vol. 104, No. 2, 07.02.2019, p. 348-355.

Research output: Contribution to journalArticle

Harvard

Dorval, G, Kuzmuk, V, Gribouval, O, Welsh, G, Bierzynska, A, Schmitt, A, Miserey-Lenkei, S, Koziell, A, Haq, S, Benmerah, A, Mollet, G, Boyer, O, Saleem, M & Antignac, C 2019, 'TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways', American Journal of Human Genetics, vol. 104, no. 2, pp. 348-355. https://doi.org/10.1016/j.ajhg.2018.12.016

APA

Dorval, G., Kuzmuk, V., Gribouval, O., Welsh, G., Bierzynska, A., Schmitt, A., ... Antignac, C. (2019). TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. American Journal of Human Genetics, 104(2), 348-355. https://doi.org/10.1016/j.ajhg.2018.12.016

Vancouver

Dorval G, Kuzmuk V, Gribouval O, Welsh G, Bierzynska A, Schmitt A et al. TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. American Journal of Human Genetics. 2019 Feb 7;104(2):348-355. https://doi.org/10.1016/j.ajhg.2018.12.016

Author

Dorval, Guillaume ; Kuzmuk, Valeryia ; Gribouval, Olivier ; Welsh, Gavin ; Bierzynska, Agnieszka ; Schmitt, Alain ; Miserey-Lenkei, Stephanie ; Koziell, Ania ; Haq, Shuman ; Benmerah, Alexandre ; Mollet, Geraldine ; Boyer, Olivia ; Saleem, Moin ; Antignac, Corinne. / TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 2. pp. 348-355.

Bibtex

@article{c685302de6bc46f8b52449bbbcfab796,
title = "TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways",
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 = "podocyte, nephrotic syndrome, endocytosis, recycling, inherited, rab11, child trafficking, genetic",
author = "Guillaume Dorval and Valeryia Kuzmuk and Olivier Gribouval and Gavin Welsh and Agnieszka Bierzynska and Alain Schmitt and Stephanie Miserey-Lenkei and Ania Koziell and Shuman Haq and Alexandre Benmerah and Geraldine Mollet and Olivia Boyer and Moin Saleem and Corinne Antignac",
year = "2019",
month = "2",
day = "7",
doi = "10.1016/j.ajhg.2018.12.016",
language = "English",
volume = "104",
pages = "348--355",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways

AU - Dorval, Guillaume

AU - Kuzmuk, Valeryia

AU - Gribouval, Olivier

AU - Welsh, Gavin

AU - Bierzynska, Agnieszka

AU - Schmitt, Alain

AU - Miserey-Lenkei, Stephanie

AU - Koziell, Ania

AU - Haq, Shuman

AU - Benmerah, Alexandre

AU - Mollet, Geraldine

AU - Boyer, Olivia

AU - Saleem, Moin

AU - Antignac, Corinne

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

KW - podocyte

KW - nephrotic syndrome

KW - endocytosis

KW - recycling

KW - inherited

KW - rab11

KW - child trafficking

KW - genetic

UR - http://www.scopus.com/inward/record.url?scp=85060993985&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.12.016

DO - 10.1016/j.ajhg.2018.12.016

M3 - Article

VL - 104

SP - 348

EP - 355

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -