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

Authors
 Maxence S. Macia  ;  Jan Halbritter  ;  Marion Delous  ;  Cecilie Bredrup  ;  Arthur Gutter  ;  Emilie Filhol  ;  Anne E.C. Mellgren  ;  Sabine Leh  ;  Albane Bizet  ;  Daniela A. Braun  ;  Heon Y. Gee  ;  Flora Silbermann  ;  Charline Henry  ;  Pauline Krug  ;  Christine Bole-Feysot  ;  Patrick Nitschke  ;  Dominique Joly  ;  Philippe Nicoud  ;  Andre´ Paget  ;  Heidi Haugland  ;  Damien Brackmann  ;  Nayir Ahmet  ;  Richard Sandford  ;  Nurcan Cengiz  ;  Per M. Knappskog  ;  Helge Boman  ;  Bolan Linghu  ;  Fan Yang  ;  Edward J. Oakeley  ;  Pierre Saint Me´zard  ;  Andreas W. Sailer  ;  Stefan Johansson  ;  Eyvind Rødahl  ;  Sophie Saunier  ;  Friedhelm Hildebrandt  ;  Alexandre Benmerah 
Citation
 AMERICAN JOURNAL OF HUMAN GENETICS, Vol.100(2) : 323-333, 2017 
Journal Title
 AMERICAN JOURNAL OF HUMAN GENETICS 
ISSN
 0002-9297 
Issue Date
2017
MeSH
Adolescent ; Alleles ; Animals ; Child ; Cilia/genetics ; DNA Damage/genetics ; Disease Models, Animal ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Fibrosis ; Gene Expression Regulation ; Humans ; Intracellular Signaling Peptides and Proteins/genetics* ; Kidney/cytology ; Kidney/metabolism ; Kidney Diseases, Cystic/congenital* ; Kidney Diseases, Cystic/diagnosis ; Kidney Diseases, Cystic/genetics ; Kidney Failure, Chronic/diagnosis ; Kidney Failure, Chronic/genetics ; Mice ; Mice, Knockout ; Mitosis ; Mutation ; NIH 3T3 Cells ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Pedigree ; Phenotype ; Signal Transduction ; Spindle Poles/metabolism ; Young Adult ; Zebrafish
Keywords
DNA damage ; MAP kinase ; MAPKBP1 ; WDR62 ; ciliopathy ; digenism ; kidney ; mitotic spindle ; nephronophthisis ; retinitis pigmentosa
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S0002929717300319
DOI
10.1016/j.ajhg.2016.12.011
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154291
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