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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; Lusk, C Patrick; 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; Serdaroglu, Erkin; Alhasan, Khalid A; Hashem, Mais; Goncalves, Sara; Ariceta, Gema; Ubetagoyena, Mercedes; Antonin, Wolfram; Baig, Shahid Mahmood; Alkuraya, Fowzan S.
Afiliación
  • Braun DA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Lovric S; Department of Internal Medicine D, University Hospital of Münster, Münster, Germany.
  • Schapiro D; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Schneider R; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Marquez J; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Asif M; Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Hussain MS; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Daga A; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Widmeier E; Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan.
  • Rao J; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Ashraf S; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Tan W; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Lusk CP; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Kolb A; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Jobst-Schwan T; Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.
  • Schmidt JM; Shanghai Kidney Development and Pediatric Kidney Disease Research Center, Shanghai, China.
  • Hoogstraten CA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Eddy K; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Kitzler TM; Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • Shril S; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Moawia A; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Schrage K; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Khayyat AIA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Lawson JA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Gee HY; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Warejko JK; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Hermle T; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Majmundar AJ; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Hugo H; Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan.
  • Budde B; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Motameny S; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Altmüller J; Biochemistry Department, King Saud University, Riyadh, Saudi Arabia.
  • Noegel AA; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Fathy HM; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Gale DP; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Waseem SS; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Khan A; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Kerecuk L; Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Hashmi S; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Mohebbi N; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Ettenger R; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Serdaroglu E; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Alhasan KA; Institute of Human Genetics, University of Cologne, Cologne, Germany.
  • Hashem M; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
  • Goncalves S; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
  • Ariceta G; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Ubetagoyena M; Pediatric Nephrology Unit, Alexandria Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
  • Antonin W; Centre for Nephrology, University College London, Royal Free Hospital, London, United Kingdom.
  • Baig SM; Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • Alkuraya FS; Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
J Clin Invest ; 128(10): 4313-4328, 2018 10 01.
Article en En | MEDLINE | ID: mdl-30179222
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Xenopus / Proteínas de Complejo Poro Nuclear / Proteínas de Pez Cebra / Síndrome Nefrótico Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Xenopus / Proteínas de Complejo Poro Nuclear / Proteínas de Pez Cebra / Síndrome Nefrótico Límite: Animals / Humans Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos