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Functional analysis of BMP4 mutations identified in pediatric CAKUT patients

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Abstract

Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.

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Acknowledgement

The authors acknowledge the Nikon Imaging Center at the University of Heidelberg. Financial support for this study was obtained from the Thyssen Foundation (AZ-10.07.2.173), the Dietmar Hopp Foundation, and the European Commission (5th Framework Program, QLG1-CT-2002 00908).

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Author notes

  1. Stefanie Weber

    Present address: University of Essen Children’s Hospital, Hufelandstrasse 55, 45122, Essen, Germany

Authors and Affiliations

  1. Pediatric Nephrology, University of Heidelberg Children’s Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Mansoureh Tabatabaeifar, Otto Mehls, Franz Schaefer & Stefanie Weber

  2. Pediatric Nephrology, University of Marburg Children’s Hospital, Marburg, Germany

    Karl-Peter Schlingmann

  3. Nephrology and Kidney Transplantation Department, Children’s Memorial Health Hospital Warsaw, Warsaw, Poland

    Mieczyslaw Litwin

  4. Department of Pediatrics, Istanbul Medical Faculty, University of Istanbul, Istanbul, Turkey

    Sevinc Emre

  5. Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Aysin Bakkaloglu

  6. INSERM U574, Hôpital Necker-Enfants Malades, Paris, France

    Corinne Antignac

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  1. Mansoureh Tabatabaeifar
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  2. Karl-Peter Schlingmann
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  9. Stefanie Weber
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ESCAPE Trial Group

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Correspondence to Stefanie Weber.

Additional information

ESCAPE Network collaborators: A. Anarat (Adana); A. Bakkaloglu, F. Ozaltin (Ankara); A. Peco-Antic (Belgrade); U. Querfeld, J. Gellermann (Berlin); P. Sallay (Budapest); D. Drozdz (Cracow); K.-E. Bonzel, A.-M. Wingen (Essen); A. Zurowska, I. Balasz (Gdansk); F. Perfumo, A. Canepa (Genoa); D.E. Müller-Wiefel, K. Zepf (Hamburg); G. Offner, B. Enke (Hannover); O. Mehls, F. Schaefer, E. Wühl, C. Hadtstein (Heidelberg); U. Berg, G. Celsi (Huddinge); S. Emre, A. Sirin, I. Bilge (Istanbul); S. Çaliskan (Istanbul-Cerrahpasa); S. Mir, E. Serdaroglu (Izmir); C. Greiner, H. Eichstädt, S. Wygoda (Leipzig); K. Hohbach-Hohenfellner (Mainz); N. Jeck, G. Klaus (Marburg); A. Appiani, G. Ardissino, S. Testa (Milano); G. Montini (Padova); C. Antignac, P. Niaudet, M. Charbit (Paris); J. Dusek (Prague); A. Caldas-Afonso, A. Teixeira (Porto); S. Picca, C. Matteucci (Rome); M. Wigger (Rostock); M. Fischbach, J. Terzic (Strasbourg); J. Fydryk, T. Urasinski (Szezecin); R. Coppo, L. Peruzzi (Torino); A. Jankauskiene (Vilnius); M. Litwin, M. Abuauba, R. Grenda (Warszawa); K. Arbeiter (Vienna); T.J. Neuhaus (Zurich).

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Tabatabaeifar, M., Schlingmann, KP., Litwin, M. et al. Functional analysis of BMP4 mutations identified in pediatric CAKUT patients. Pediatr Nephrol 24, 2361–2368 (2009). https://doi.org/10.1007/s00467-009-1287-6

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  • DOI: https://doi.org/10.1007/s00467-009-1287-6

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