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@ARTICLE{Kampf:614406,
      author       = {Kampf, Lina L. and Schneider, Ronen and Gerstner, Lea and
                      Thünauer, Roland and Chen, Mengmeng and Helmstädter,
                      Martin and Amar, Ali and Onuchic-Whitford, Ana C. and Loza
                      Munarriz, Reyner and Berdeli, Afig and Müller, Dominik and
                      Schrezenmeier, Eva and Budde, Klemens and Mane, Shrikant and
                      Laricchia, Kristen M. and Rehm, Heidi L. and MacArthur,
                      Daniel G. and Lifton, Richard P. and Walz, Gerd and Römer,
                      Winfried and Bergmann, Carsten and Hildebrandt, Friedhelm
                      and Hermle, Tobias},
      title        = {{TBC}1{D}8{B} {M}utations {I}mplicate {RAB}11-{D}ependent
                      {V}esicular {T}rafficking in the {P}athogenesis of
                      {N}ephrotic {S}yndrome},
      journal      = {Journal of the American Society of Nephrology},
      volume       = {30},
      number       = {12},
      issn         = {1046-6673},
      address      = {[Erscheinungsort nicht ermittelbar]},
      publisher    = {Ovid},
      reportid     = {PUBDB-2024-05873},
      pages        = {2338 - 2353},
      year         = {2019},
      note         = {This research was supported by grants from the Deutsche
                      Forschungsgemeinschaft to Dr. Hermle (HE 7456/3-1) . Dr.
                      Bergmann acknowledges support from the Deutsche
                      Forschungsgemeinschaft Collaborative Research Centre (KIDGEM
                      1140) and the Federal Ministry of Education and Research
                      (01GM1515C).},
      abstract     = {AbstractSignificance Statement The discovery of monogenic
                      causes of nephrotic syndrome led to insights about the role
                      of podocytes and the slit diaphragm in the pathogenesis of
                      the disease. The authors describe novel mutations in TBC1D8B
                      in five families with steroid-resistant nephrotic syndrome.
                      TBC1D8B binds to active RAB11A and RAB11B. Silencing TBC1D8B
                      leads to upregulation of RAB11-dependent processes
                      suggesting TBC1D8B inhibits RAB11. TBC1D8B also interacts
                      and colocalizes with the slit diaphragm protein nephrin.
                      Silencing TBC1D8B in podocyte-like Drosophila nephrocytes
                      causes mistrafficking of fly nephrin. Nephrin trafficking in
                      Drosophila requires Rab11, whereas overexpression of Rab11
                      causes a similar phenotype as TBC1D8B silencing. These
                      findings implicate regulation of RAB11-dependent vesicular
                      trafficking by TBC1D8B as a novel pathogenetic pathway in
                      nephrotic syndrome.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.},
      cin          = {CSSB-CF-ALFM},
      ddc          = {610},
      cid          = {I:(DE-H253)CSSB-CF-ALFM-20210629},
      pnm          = {899 - ohne Topic (POF4-899) / DFG project
                      G:(GEPRIS)39236281 - EXC 294: BIOSS Zentrum für Biologische
                      Signalstudien - von der Analyse zur Synthese (39236281)},
      pid          = {G:(DE-HGF)POF4-899 / G:(GEPRIS)39236281},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31732614},
      UT           = {WOS:000508269600010},
      doi          = {10.1681/ASN.2019040414},
      url          = {https://bib-pubdb1.desy.de/record/614406},
}