Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

Daniela A. Braun, Svjetlana Lovric, David Schapiro, Ronen Schneider, Jonathan Marquez, Maria Asif, Muhammad Sajid Hussain, Ankana Daga, Eugen Widmeier, Jia Rao, Shazia Ashraf, Weizhen Tan, C. Patrick Lusk, Amy Kolb, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Charlotte A. Hoogstraten, Kaitlyn Eddy, Thomas M. Kitzler, Shirlee Shril & 38 others Abubakar Moawia, Kathrin Schrage, Arwa Ishaq A. Khayyat, Jennifer A. Lawson, Heon Yung Gee, Jillian K. Warejko, Tobias Hermle, Amar J. Majmundar, Hannah Hugo, Birgit Budde, Susanne Motameny, Janine Altmüller, Angelika Anna Noegel, Hanan M. Fathy, Daniel P. Gale, Syeda Seema Waseem, Ayaz Khan, Larissa Kerecuk, Seema Hashmi, Nilufar Mohebbi, Robert Ettenger, Erkin Serdaroğlu, Khalid A. Alhasan, Mais Hashem, Sara Goncalves, Gema Ariceta, Mercedes Ubetagoyena, Wolfram Antonin, Shahid Mahmood Baig, Fowzan S. Alkuraya, Qian Shen, Hong Xu, Corinne Antignac, Richard P. Lifton, Shrikant Mane, Peter Nürnberg, Mustafa K. Khokha, Friedhelm Hildebrandt

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)4313-4328
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

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Nuclear Pore
Nephrotic Syndrome
Steroids
Mutation
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Components
Phenotype
Morpholinos
Podocytes
Messenger RNA
Essential Genes
Zebrafish
Xenopus
Chronic Kidney Failure
Alleles
Survival

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Braun, D. A., Lovric, S., Schapiro, D., Schneider, R., Marquez, J., Asif, M., ... Hildebrandt, F. (2018). Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. Journal of Clinical Investigation, 128(10), 4313-4328. https://doi.org/10.1172/JCI98688
Braun, Daniela A. ; Lovric, Svjetlana ; Schapiro, David ; Schneider, Ronen ; Marquez, Jonathan ; Asif, Maria ; Hussain, Muhammad Sajid ; Daga, Ankana ; Widmeier, Eugen ; Rao, Jia ; Ashraf, Shazia ; Tan, Weizhen ; Patrick Lusk, C. ; Kolb, Amy ; Jobst-Schwan, Tilman ; 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 ; Warejko, Jillian K. ; Hermle, Tobias ; Majmundar, Amar J. ; Hugo, Hannah ; Budde, Birgit ; Motameny, Susanne ; Altmüller, Janine ; Noegel, Angelika Anna ; Fathy, Hanan M. ; Gale, Daniel P. ; Waseem, Syeda Seema ; Khan, Ayaz ; Kerecuk, Larissa ; Hashmi, Seema ; Mohebbi, Nilufar ; Ettenger, Robert ; Serdaroğlu, Erkin ; 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 ; Nürnberg, Peter ; Khokha, Mustafa K. ; Hildebrandt, Friedhelm. / Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 10. pp. 4313-4328.
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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.",
author = "Braun, {Daniela A.} and Svjetlana Lovric and David Schapiro and Ronen Schneider and Jonathan Marquez and Maria Asif and Hussain, {Muhammad Sajid} and Ankana Daga and Eugen Widmeier and Jia Rao and Shazia Ashraf and Weizhen Tan and {Patrick Lusk}, C. and Amy Kolb and Tilman Jobst-Schwan and Schmidt, {Johanna Magdalena} and Hoogstraten, {Charlotte A.} and Kaitlyn Eddy and Kitzler, {Thomas M.} and Shirlee Shril and Abubakar Moawia and Kathrin Schrage and Khayyat, {Arwa Ishaq A.} and Lawson, {Jennifer A.} and Gee, {Heon Yung} and Warejko, {Jillian K.} and Tobias Hermle and Majmundar, {Amar J.} and Hannah Hugo and Birgit Budde and Susanne Motameny and Janine Altm{\"u}ller and Noegel, {Angelika Anna} and Fathy, {Hanan M.} and Gale, {Daniel P.} and Waseem, {Syeda Seema} and Ayaz Khan and Larissa Kerecuk and Seema Hashmi and Nilufar Mohebbi and Robert Ettenger and Erkin Serdaroğlu and Alhasan, {Khalid A.} and Mais Hashem and Sara Goncalves and Gema Ariceta and Mercedes Ubetagoyena and Wolfram Antonin and Baig, {Shahid Mahmood} and Alkuraya, {Fowzan S.} and Qian Shen and Hong Xu and Corinne Antignac and Lifton, {Richard P.} and Shrikant Mane and Peter N{\"u}rnberg and Khokha, {Mustafa K.} and Friedhelm Hildebrandt",
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Braun, DA, Lovric, S, Schapiro, D, Schneider, R, Marquez, J, Asif, M, Hussain, MS, Daga, A, Widmeier, E, Rao, J, Ashraf, S, Tan, W, Patrick Lusk, C, Kolb, A, Jobst-Schwan, T, Schmidt, JM, Hoogstraten, CA, Eddy, K, Kitzler, TM, Shril, S, Moawia, A, Schrage, K, Khayyat, AIA, Lawson, JA, Gee, HY, Warejko, JK, Hermle, T, Majmundar, AJ, Hugo, H, Budde, B, Motameny, S, Altmüller, J, Noegel, AA, Fathy, HM, Gale, DP, Waseem, SS, Khan, A, Kerecuk, L, Hashmi, S, Mohebbi, N, Ettenger, R, Serdaroğlu, E, Alhasan, KA, Hashem, M, Goncalves, S, Ariceta, G, Ubetagoyena, M, Antonin, W, Baig, SM, Alkuraya, FS, Shen, Q, Xu, H, Antignac, C, Lifton, RP, Mane, S, Nürnberg, P, Khokha, MK & Hildebrandt, F 2018, 'Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome', Journal of Clinical Investigation, vol. 128, no. 10, pp. 4313-4328. https://doi.org/10.1172/JCI98688

Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. / Braun, Daniela A.; Lovric, Svjetlana; Schapiro, David; Schneider, Ronen; Marquez, Jonathan; Asif, Maria; Hussain, Muhammad Sajid; Daga, Ankana; Widmeier, Eugen; Rao, Jia; Ashraf, Shazia; Tan, Weizhen; Patrick Lusk, C.; Kolb, Amy; Jobst-Schwan, Tilman; 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; Warejko, Jillian K.; Hermle, Tobias; Majmundar, Amar J.; Hugo, Hannah; Budde, Birgit; Motameny, Susanne; Altmüller, Janine; Noegel, Angelika Anna; Fathy, Hanan M.; Gale, Daniel P.; Waseem, Syeda Seema; Khan, Ayaz; Kerecuk, Larissa; Hashmi, Seema; Mohebbi, Nilufar; Ettenger, Robert; Serdaroğlu, Erkin; 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; Nürnberg, Peter; Khokha, Mustafa K.; Hildebrandt, Friedhelm.

In: Journal of Clinical Investigation, Vol. 128, No. 10, 01.10.2018, p. 4313-4328.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome

AU - Braun, Daniela A.

AU - Lovric, Svjetlana

AU - Schapiro, David

AU - Schneider, Ronen

AU - Marquez, Jonathan

AU - Asif, Maria

AU - Hussain, Muhammad Sajid

AU - Daga, Ankana

AU - Widmeier, Eugen

AU - Rao, Jia

AU - Ashraf, Shazia

AU - Tan, Weizhen

AU - Patrick Lusk, C.

AU - Kolb, Amy

AU - Jobst-Schwan, Tilman

AU - Schmidt, Johanna Magdalena

AU - Hoogstraten, Charlotte A.

AU - Eddy, Kaitlyn

AU - Kitzler, Thomas M.

AU - Shril, Shirlee

AU - Moawia, Abubakar

AU - Schrage, Kathrin

AU - Khayyat, Arwa Ishaq A.

AU - Lawson, Jennifer A.

AU - Gee, Heon Yung

AU - Warejko, Jillian K.

AU - Hermle, Tobias

AU - Majmundar, Amar J.

AU - Hugo, Hannah

AU - Budde, Birgit

AU - Motameny, Susanne

AU - Altmüller, Janine

AU - Noegel, Angelika Anna

AU - Fathy, Hanan M.

AU - Gale, Daniel P.

AU - Waseem, Syeda Seema

AU - Khan, Ayaz

AU - Kerecuk, Larissa

AU - Hashmi, Seema

AU - Mohebbi, Nilufar

AU - Ettenger, Robert

AU - Serdaroğlu, Erkin

AU - Alhasan, Khalid A.

AU - Hashem, Mais

AU - Goncalves, Sara

AU - Ariceta, Gema

AU - Ubetagoyena, Mercedes

AU - Antonin, Wolfram

AU - Baig, Shahid Mahmood

AU - Alkuraya, Fowzan S.

AU - Shen, Qian

AU - Xu, Hong

AU - Antignac, Corinne

AU - Lifton, Richard P.

AU - Mane, Shrikant

AU - Nürnberg, Peter

AU - Khokha, Mustafa K.

AU - Hildebrandt, Friedhelm

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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DO - 10.1172/JCI98688

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Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M et al. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. Journal of Clinical Investigation. 2018 Oct 1;128(10):4313-4328. https://doi.org/10.1172/JCI98688