Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment.
Journalkidney international8.945Date
2020 Jun 04
5 months ago
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Journal Article
2020-10 / 98 : 958-969
Schönauer R 1, Jin W 1, Ertel A 1, Nemitz-Kliemchen M 1, Panitz N 1, Hantmann E 1, Seidel A 1, Braun DA 2, Shril S 2, Hansen M 3, Shahzad K 4, Sandford R 5, Saunier S 6, Benmerah A 6, Bergmann C 7, Hildebrandt F 2, Halbritter J 8
  • 2. Department of Medicine, Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • 3. Kuratorium für Dialyse und Nierentransplantation e. V. Center of Pediatric Nephrology, Clementine Children's Hospital, Frankfurt, Germany.
  • 4. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, Leipzig, Germany.
  • 5. Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
  • 6. Université de Paris, Imagine Institute, Laboratory of inherited kidney diseases, INSERM UMR 1163, Paris, France.
  • 7. Center for Human Genetics, Bioscientia, Ingelheim, Germany; Department of Medicine, University Hospital Freiburg, Freiburg, Germany; Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.
  • 8. Division of Nephrology, University Hospital Leipzig Medical Center, Leipzig, Germany. Electronic address: [email protected]
Biallelic mutations in MAPKBP1 were recently associated with late-onset cilia-independent nephronophthisis. MAPKBP1 was found at mitotic spindle poles but could not be detected at primary cilia or centrosomes. Here, by identification and characterization of novel MAPKBP1 variants, we aimed at further investigating its role in health and disease. Genetic analysis was done by exome sequencing, homozygosity mapping, and a targeted kidney gene panel while coimmunoprecipitation was used to explore wild-type and mutant protein-protein interactions. Expression of MAPKBP1 in non-ciliated HeLa and ciliated inner medullary collecting duct cells enabled co-localization studies by fluorescence microscopy. By next generation sequencing, we identified two novel homozygous MAPKBP1 splice-site variants in patients with nephronophthisis-related chronic kidney disease. Splice-site analyses revealed truncation of C-terminal coiled-coil domains and patient-derived deletion constructs lost their ability to homodimerize and heterodimerize with paralogous WDR62. While wild-type MAPKBP1 exhibited centrosomal, basal body, and microtubule association, mutant proteins lost the latter and showed reduced recruitment to cell cycle dependent centriolar structures. Wild-type and mutant proteins had no reciprocal influence upon co-expression excluding dominant negative effects. Thus, MAPKBP1 appears to be a novel microtubule-binding protein with cell cycle dependent centriolar localization. Truncation of its coiled-coil domain is enough to abrogate its dimerization and results in severely disturbed intracellular localizations. Delineating the impact of impaired dimerization on cell cycle regulation and intracellular kidney signaling may provide new insights into common mechanisms of kidney degeneration. Thus, due to milder clinical presentation, MAPKBP1-associated nephronophthisis should be considered in adult patients with otherwise unexplained chronic kidney disease.
Keywords: MAPKBP1 WDR62 centrosome chronic kidney disease cilia microtubules nephronophthisis scoliosis tubulointerstitial nephritis
Kidney Intkidney international
LocationUnited States

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