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Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.

Nephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: "NPHP1-4-8" functioning at the apical surface, "NPHP5-6" at centrosomes, and "MKS" linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes, and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.

Pubmed ID: 21565611

Authors

  • Sang L
  • Miller JJ
  • Corbit KC
  • Giles RH
  • Brauer MJ
  • Otto EA
  • Baye LM
  • Wen X
  • Scales SJ
  • Kwong M
  • Huntzicker EG
  • Sfakianos MK
  • Sandoval W
  • Bazan JF
  • Kulkarni P
  • Garcia-Gonzalo FR
  • Seol AD
  • O'Toole JF
  • Held S
  • Reutter HM
  • Lane WS
  • Rafiq MA
  • Noor A
  • Ansar M
  • Devi AR
  • Sheffield VC
  • Slusarski DC
  • Vincent JB
  • Doherty DA
  • Hildebrandt F
  • Reiter JF
  • Jackson PK

Journal

Cell

Publication Data

May 13, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: CA112369
  • Agency: NIDDK NIH HHS, Id: DK071108
  • Agency: NIDDK NIH HHS, Id: DK090917
  • Agency: NIDDK NIH HHS, Id: DK1068306
  • Agency: NIDDK NIH HHS, Id: DK1069274
  • Agency: NIGMS NIH HHS, Id: GM07365-33
  • Agency: NIDDK NIH HHS, Id: K08 DK071108
  • Agency: NIDDK NIH HHS, Id: K08 DK071108-01A1
  • Agency: NCRR NIH HHS, Id: KL2 RR025015
  • Agency: NCRR NIH HHS, Id: KL2RR025015
  • Agency: Canadian Institutes of Health Research, Id: MOP-102758
  • Agency: NIAMS NIH HHS, Id: R01 AR054396
  • Agency: NIAMS NIH HHS, Id: R01 AR054396-01A1
  • Agency: NCI NIH HHS, Id: R01 CA112369
  • Agency: NCI NIH HHS, Id: R01 CA112369-01
  • Agency: NIDDK NIH HHS, Id: R01 DK068306
  • Agency: NEI NIH HHS, Id: R01 EY011298
  • Agency: NEI NIH HHS, Id: R01 EY011298-04
  • Agency: NEI NIH HHS, Id: R01 EY017168
  • Agency: NEI NIH HHS, Id: R01 EY017168-01A2
  • Agency: NIGMS NIH HHS, Id: R01 GM095941
  • Agency: NIGMS NIH HHS, Id: R01 GM095941-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS064077
  • Agency: NINDS NIH HHS, Id: R01 NS064077-01A2
  • Agency: NIAMS NIH HHS, Id: R01-AR054396
  • Agency: NEI NIH HHS, Id: R01-EY017168
  • Agency: NEI NIH HHS, Id: R01-EY11298
  • Agency: NINDS NIH HHS, Id: R01NS064077
  • Agency: NIDDK NIH HHS, Id: RC4 DK090917
  • Agency: NIDDK NIH HHS, Id: RC4 DK090917-01
  • Agency: NHLBI NIH HHS, Id: T32 HL007121
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Centrosome
  • Cilia
  • Ciliary Motility Disorders
  • Encephalocele
  • Hedgehog Proteins
  • Humans
  • Kidney Diseases, Cystic
  • Membrane Proteins
  • Mice
  • NIH 3T3 Cells
  • Nerve Tissue Proteins
  • Polycystic Kidney Diseases
  • Signal Transduction
  • Zebrafish