title: Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis.
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.
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Maxence S
authors.initials: MS
authors.lastname: Macia
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Delous
authors.affiliation: Department of Ophthalmology, Haukeland University Hospital, 5021 Bergen, Norway; Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bredrup
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Arthur
authors.initials: A
authors.lastname: Gutter
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Filhol
authors.affiliation: 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.
authors.forename: Anne E C
authors.initials: AEC
authors.lastname: Mellgren
authors.affiliation: Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Sabine
authors.initials: S
authors.lastname: Leh
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Albane
authors.initials: A
authors.lastname: Bizet
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Heon Y
authors.initials: HY
authors.lastname: Gee
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Silbermann
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Charline
authors.initials: C
authors.lastname: Henry
authors.affiliation: 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.
authors.forename: Pauline
authors.initials: P
authors.lastname: Krug
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Inserm UMR-1163, Genomic Core Facility, 75015 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Bioinformatics Core Facility, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: Nephrology Department, Necker -Enfants Malades Hospital, 75015 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Joly
authors.affiliation: Hemodialysis-Nephrology Department, Mont-Blanc Hospitals, 74700 Sallanches, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Nicoud
authors.affiliation: Hemodialysis-Nephrology Department, Mont-Blanc Hospitals, 74700 Sallanches, France.
authors.forename: André
authors.initials: A
authors.lastname: Paget
authors.affiliation: Department of Ophthalmology, Førde Central Hospital, 6812 Førde, Norway.
authors.forename: Heidi
authors.initials: H
authors.lastname: Haugland
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Damien
authors.initials: D
authors.lastname: Brackmann
authors.affiliation: University of Istanbul, 34452 Istanbul, Turkey.
authors.forename: Nayir
authors.initials: N
authors.lastname: Ahmet
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, CB2 0QQ Cambridge, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandford
authors.affiliation: Baskent University, 06810 Ankara, Turkey.
authors.forename: Nurcan
authors.initials: N
authors.lastname: Cengiz
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Boman
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Bolan
authors.initials: B
authors.lastname: Linghu
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Saint Mézard
authors.affiliation: Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
authors.affiliation: Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Department of Ophthalmology, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.
authors.forename: Eyvind
authors.initials: E
authors.lastname: Rødahl
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France. Electronic address: sophie.saunier@inserm.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: INSERM, UMR-1163, Laboratory of Inherited Kidney Diseases, 75015 Paris, France; Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D018797:Cell Cycle Proteins; D002648:Child; D002923:Cilia / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D052177:Kidney Diseases, Cystic / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009154:Mutation; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction; D064047:Spindle Poles / Q000378:metabolism; D055815:Young Adult; D015027:Zebrafish
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C580778:MAPKBP1 protein, human; C121624:Mapkbp1 protein, mouse; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human
keywords: DNA damage; MAP kinase; MAPKBP1; WDR62; ciliopathy; digenism; kidney; mitotic spindle; nephronophthisis; retinitis pigmentosa