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.

DOI: 10.1016/j.cell.2011.04.019

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@article{Sang2011MappingTN, title={Mapping the NPHP-JBTS-MKS Protein Network Reveals Ciliopathy Disease Genes and Pathways}, author={Liyun Sang and Julie J. Miller and Kevin C. Corbit and Rachel H Giles and Matthew J. Brauer and Edgar A. Otto and Lisa M. Baye and Xiaohui Wen and Suzie J Scales and Mandy Kwong and Erik G. Huntzicker and Mindan K. Sfakianos and Wendy Sandoval and J. Fernando Bazan and Priya Kulkarni and Francesc R. Garcia-Gonzalo and Allen D. Seol and John F. O'Toole and Susanne Held and Heiko Reutter and William S. Lane and Muhammad Arshad Rafiq and Abdul Rahmand Noor and Muhammad Ansar and Akella Radha Rama Devi and Val C. Sheffield and Diane C. Slusarski and John B . Vincent and Daniel A Doherty and Friedhelm Hildebrandt and Jeremy F Reiter and Peter Kent Jackson}, journal={Cell}, year={2011}, volume={145}, pages={513-528} }