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.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Dorval G,Kuzmuk V,Gribouval O,Welsh GI,Bierzynska A,Schmitt A,Miserey-Lenkei S,Koziell A,Haq S,Benmerah A,Mollet G,Boyer O,Saleem MA,Antignac Cdoi
10.1016/j.ajhg.2018.12.016subject
Has Abstractpub_date
2019-02-07 00:00:00pages
348-355issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(18)30469-5journal_volume
104pub_type
杂志文章abstract：:The highly polymorphic locus D2S3 is revealed by three single-copy probes from cosmid C1-5. These probes, 1-30, 1-32, and 2-96, collectively reveal seven restriction fragment length polymorphisms. Fifty-three of 56 unrelated individuals (93%) were heterozygous at one or more of the seven loci, making the compound locu...
journal_title：American journal of human genetics
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更新日期：1986-03-01 00:00:00
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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更新日期：1993-09-01 00:00:00
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journal_title：American journal of human genetics
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更新日期：1991-08-01 00:00:00
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journal_title：American journal of human genetics
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更新日期：1984-07-01 00:00:00
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journal_title：American journal of human genetics
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更新日期：1997-02-01 00:00:00
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journal_title：American journal of human genetics
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doi：
更新日期：1992-07-01 00:00:00
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journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1989-03-01 00:00:00
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journal_title：American journal of human genetics
pub_type： 杂志文章
doi：
更新日期：1984-11-01 00:00:00
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journal_title：American journal of human genetics
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doi：
更新日期：1981-03-01 00:00:00
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journal_title：American journal of human genetics
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doi：
更新日期：1993-05-01 00:00:00
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journal_title：American journal of human genetics
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journal_title：American journal of human genetics
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doi：
更新日期：1986-04-01 00:00:00
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journal_title：American journal of human genetics
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doi：
更新日期：1983-09-01 00:00:00
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