Braun, Daniela A., Lovric, Svjetlana, Schapiro, David, Schneider, Ronen, Marquez, Jonathan ORCID: 0000-0003-3377-7599, Asif, Maria, Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809, Daga, Ankana, Widmeier, Eugen ORCID: 0000-0002-7773-5190, Rao, Jia, Ashraf, Shazia, Tan, Weizhen, Lusk, C. Patrick, Kolb, Amy, Jobst-Schwan, Tilman ORCID: 0000-0001-9802-6783, Schmidt, Johanna Magdalena, Hoogstraten, Charlotte A., Eddy, Kaitlyn, Kitzler, Thomas M., Shril, Shirlee, Moawia, Abubakar, Schrage, Kathrin, Khayyat, Arwa Ishaq A., Lawson, Jennifer A., Gee, Heon Yung ORCID: 0000-0002-8741-6177, Warejko, Jillian K., Hermle, Tobias ORCID: 0000-0002-0441-7749, Majmundar, Amar J., Hugo, Hannah, Budde, Birgit, Motameny, Susanne, Altmueller, Janine, Noegel, Angelika Anna, Fathy, Hanan M., Gale, Daniel P., Waseem, Syeda Seema, Khan, Ayaz, Kerecuk, Larissa, Hashmi, Seema, Mohebbi, Nilufar, Ettenger, Robert, Serdaroglu, Erkin ORCID: 0000-0002-6863-8866, Alhasan, Khalid A., Hashem, Mais, Goncalves, Sara, Ariceta, Gema, Ubetagoyena, Mercedes, Antonin, Wolfram, Baig, Shahid Mahmood, Alkuraya, Fowzan S., Shen, Qian, Xu, Hong, Antignac, Corinne, Lifton, Richard P., Mane, Shrikant, Nuernberg, Peter, Khokha, Mustafa K. and Hildebrandt, Friedhelm (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J. Clin. Invest., 128 (10). S. 4313 - 4329. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained, Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braun, Daniela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lovric, SvjetlanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schapiro, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, RonenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marquez, JonathanUNSPECIFIEDorcid.org/0000-0003-3377-7599UNSPECIFIED
Asif, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
Daga, AnkanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widmeier, EugenUNSPECIFIEDorcid.org/0000-0002-7773-5190UNSPECIFIED
Rao, JiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ashraf, ShaziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, WeizhenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lusk, C. PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolb, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jobst-Schwan, TilmanUNSPECIFIEDorcid.org/0000-0001-9802-6783UNSPECIFIED
Schmidt, Johanna MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoogstraten, Charlotte A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eddy, KaitlynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitzler, Thomas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shril, ShirleeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moawia, AbubakarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrage, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khayyat, Arwa Ishaq A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lawson, Jennifer A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gee, Heon YungUNSPECIFIEDorcid.org/0000-0002-8741-6177UNSPECIFIED
Warejko, Jillian K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hermle, TobiasUNSPECIFIEDorcid.org/0000-0002-0441-7749UNSPECIFIED
Majmundar, Amar J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hugo, HannahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fathy, Hanan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gale, Daniel P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waseem, Syeda SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khan, AyazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerecuk, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hashmi, SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohebbi, NilufarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ettenger, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serdaroglu, ErkinUNSPECIFIEDorcid.org/0000-0002-6863-8866UNSPECIFIED
Alhasan, Khalid A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hashem, MaisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goncalves, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ariceta, GemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ubetagoyena, MercedesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antonin, WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shen, QianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, HongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antignac, CorinneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lifton, Richard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mane, ShrikantUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khokha, Mustafa K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-170340
DOI: 10.1172/JCI98688
Journal or Publication Title: J. Clin. Invest.
Volume: 128
Number: 10
Page Range: S. 4313 - 4329
Date: 2018
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LARGE PAKISTANI FAMILY; LINKAGE ANALYSIS; CONSANGUINEOUS FAMILIES; CELL-DIFFERENTIATION; RHO-GTPASES; DISEASE; GENE; NUCLEOPORIN; NUP107; LEADSMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17034

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