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. Epub 2017 Jan 12.


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.

MeSH terms

  • Adolescent
  • Alleles
  • Animals
  • Cell Cycle Proteins
  • 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


  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • MAPKBP1 protein, human
  • Mapkbp1 protein, mouse
  • Nerve Tissue Proteins
  • WDR62 protein, human

Supplementary concepts

  • Nephronophthisis, familial juvenile