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TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome.

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dc.contributor.author Kampf, Lina L.
dc.contributor.author Schneider, Ronen
dc.contributor.author Gerstner, Lea
dc.contributor.author Thunauer, Roland
dc.contributor.author Chen, Mengmeng
dc.contributor.author Helmstadter, Martin
dc.contributor.author Amar, Ali
dc.contributor.author Onuchic-Whitford, Ana C.
dc.contributor.author Loza Munarriz, Reyner
dc.contributor.author Berdeli, Afig
dc.contributor.author Muller, Dominik
dc.contributor.author Schrezenmeier, Eva
dc.contributor.author Budde, Klemens
dc.contributor.author Mane, Shrikant
dc.contributor.author Laricchia, Kristen M.
dc.contributor.author Rehm, Heidi L.
dc.contributor.author MacArthur, Daniel G.
dc.contributor.author Lifton, Richard P.
dc.contributor.author Walz, Gerd
dc.contributor.author Romer, Winfried
dc.contributor.author Bergmann, Carsten
dc.contributor.author Hildebrandt, Friedhelm
dc.contributor.author Hermle, Tobias
dc.date.accessioned 2019-12-06T21:04:48Z
dc.date.available 2019-12-06T21:04:48Z
dc.date.issued 2019
dc.identifier.uri https://hdl.handle.net/20.500.12866/7629
dc.description.abstract BACKGROUND: Mutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology. METHODS: We used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes. RESULTS: We identified hemizygous missense mutations in the gene TBC1D8B in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing TBC1D8B in HEK293T cells increased basal autophagy and exocytosis, two cellular functions that are independently regulated by RAB11. This suggests that TBC1D8B plays a regulatory role by inhibiting endogenous RAB11. Coimmunoprecipitation assays showed TBC1D8B also interacts with the slit diaphragm protein nephrin, and colocalizes with it in immortalized cell lines. Overexpressed murine Tbc1d8b with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of Tbc1d8b in Drosophila impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the Drosophila ortholog of nephrin. Expression of Rab11 RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas RAB11 overexpression revealed a partial phenotypic overlap to Tbc1d8b loss of function. CONCLUSIONS: Novel mutations in TBC1D8B are monogenic causes of SRNS. This gene inhibits RAB11. Our findings suggest that RAB11-dependent vesicular nephrin trafficking plays a role in the pathogenesis of nephrotic syndrome. en_US
dc.language.iso eng
dc.publisher American Society of Nephrology
dc.relation.ispartof urn:issn:1533-3450
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Drosophila en_US
dc.subject endocytosis en_US
dc.subject genetic renal disease en_US
dc.subject nephrocyte en_US
dc.subject nephrotic syndrome en_US
dc.subject podocyte en_US
dc.title TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome. en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1681/ASN.2019040414
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.20


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