{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kampf LL"],"funding":["National Eye Institute","Deutsche Forschungsgemeinschaft","NIDDK NIH HHS","National Heart, Lung, and Blood Institute","NHGRI NIH HHS","National Institutes of Health","National Human Genome Research Institute","NIH HHS"],"pagination":["2338-2353"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6900796"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["30(12)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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 <i>in vitro</i> and in podocyte-like <i>Drosophila</i> nephrocytes.<h4>Results</h4>We identified hemizygous missense mutations in the gene <i>TBC1D8B</i> in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing <i>TBC1D8B</i> 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 <i>Tbc1d8b</i> with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of <i>Tbc1d8b</i> in <i>Drosophila</i> impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the <i>Drosophila</i> ortholog of nephrin. Expression of <i>Rab11</i> RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas <i>RAB11</i> overexpression revealed a partial phenotypic overlap to <i>Tbc1d8b</i> loss of function.<h4>Conclusions</h4>Novel mutations in <i>TBC1D8B</i> 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."],"journal":["Journal of the American Society of Nephrology : JASN"],"pubmed_title":["<i>TBC1D8B</i> Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome."],"pmcid":["PMC6900796"],"funding_grant_id":["DK007527","DK076683","R01 DK076683","U54HG006504","S10 OD018521","KIDGEM 1140","U54 HG006504","01GM1515C","P30 DK079310","UM1HG008900","HE 7456/3-1","Az: 33-7532.20","RO 4341/2-1","T32 DK007527","UM1 HG008900"],"pubmed_authors":["Walz G","Hermle T","MacArthur DG","Hildebrandt F","Onuchic-Whitford AC","Thunauer R","Chen M","Helmstadter M","Amar A","Berdeli A","Schneider R","Rehm HL","Romer W","Bergmann C","Budde K","Mane S","Gerstner L","Loza Munarriz R","Muller D","Schrezenmeier E","Laricchia KM","Lifton RP","Kampf LL"],"additional_accession":[]},"is_claimable":false,"name":"<i>TBC1D8B</i> Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome.","description":"<h4>Background</h4>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.<h4>Methods</h4>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 <i>in vitro</i> and in podocyte-like <i>Drosophila</i> nephrocytes.<h4>Results</h4>We identified hemizygous missense mutations in the gene <i>TBC1D8B</i> in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing <i>TBC1D8B</i> 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 <i>Tbc1d8b</i> with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of <i>Tbc1d8b</i> in <i>Drosophila</i> impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the <i>Drosophila</i> ortholog of nephrin. Expression of <i>Rab11</i> RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas <i>RAB11</i> overexpression revealed a partial phenotypic overlap to <i>Tbc1d8b</i> loss of function.<h4>Conclusions</h4>Novel mutations in <i>TBC1D8B</i> 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.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Dec","modification":"2024-10-15T09:12:28.765Z","creation":"2021-02-20T02:48:23Z"},"accession":"S-EPMC6900796","cross_references":{"pubmed":["31732614"],"doi":["10.1681/ASN.2019040414","10.1681/asn.2019040414"]}}