2. Academic Validation
  3. Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis

Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis

  • Am J Hum Genet. 2017 Feb 2;100(2):323-333. doi: 10.1016/j.ajhg.2016.12.011.
Maxence S Macia 1,  Jan Halbritter 2,  Marion Delous 1,  Cecilie Bredrup 3,  Arthur Gutter 1,  Emilie Filhol 1,  Anne E C Mellgren 4,  Sabine Leh 5,  Albane Bizet 1,  Daniela A Braun 6,  Heon Y Gee 6,  Flora Silbermann 1,  Charline Henry 1,  Pauline Krug 7,  Christine Bole-Feysot 8,  Patrick Nitschké 9,  Dominique Joly 10,  Philippe Nicoud 11,  André Paget 11,  Heidi Haugland 12,  Damien Brackmann 13,  Nayir Ahmet 14,  Richard Sandford 15,  Nurcan Cengiz 16,  Per M Knappskog 17,  Helge Boman 18,  Bolan Linghu 19,  Fan Yang 19,  Edward J Oakeley 20,  Pierre Saint Mézard 20,  Andreas W Sailer 20,  Stefan Johansson 17,  Eyvind Rødahl 21,  Sophie Saunier 22,  Friedhelm Hildebrandt 23,  Alexandre Benmerah 1
Affiliations

Affiliations

  • 1 INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
  • 2 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Nephrology, Department of Internal Medicine, University Clinic Leipzig, 04103 Leipzig, Germany.
  • 3 Department of Ophthalmology, Haukeland University Hospital, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
  • 4 Department of Ophthalmology, Haukeland University Hospital, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.
  • 5 Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.
  • 6 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7 INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Pediatric Nephrology Department, Necker-Enfants Malades Hospital, 75015 Paris, France.
  • 8 Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Inserm UMR-1163, Genomic Core Facility, 75015 Paris, France.
  • 9 Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Bioinformatics Core Facility, 75015 Paris, France.
  • 10 Nephrology Department, Necker -Enfants Malades Hospital, 75015 Paris, France.
  • 11 Hemodialysis-Nephrology Department, Mont-Blanc Hospitals, 74700 Sallanches, France.
  • 12 Department of Ophthalmology, Førde Central Hospital, 6812 Førde, Norway.
  • 13 Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway.
  • 14 University of Istanbul, 34452 Istanbul, Turkey.
  • 15 Academic Department of Medical Genetics, University of Cambridge, CB2 0QQ Cambridge, UK.
  • 16 Baskent University, 06810 Ankara, Turkey.
  • 17 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
  • 18 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
  • 19 Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
  • 20 Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
  • 21 Department of Ophthalmology, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.
  • 22 INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address: [email protected].
  • 23 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 28089251 DOI: 10.1016/j.ajhg.2016.12.011
Abstract

Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of Mapkbp1 in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in MAPKBP1 as a genetic cause of juvenile or late-onset and cilia-independent NPH.

Keywords

DNA damage; MAP kinase; MAPKBP1; WDR62; ciliopathy; digenism; kidney; mitotic spindle; nephronophthisis; retinitis pigmentosa.

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