Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Sang L

PROVIDER: S-EPMC3383065 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Sang Liyun L Miller Julie J JJ Corbit Kevin C KC Giles Rachel H RH Brauer Matthew J MJ Otto Edgar A EA Baye Lisa M LM Wen Xiaohui X Scales Suzie J SJ Kwong Mandy M Huntzicker Erik G EG Sfakianos Mindan K MK Sandoval Wendy W Bazan J Fernando JF Kulkarni Priya P Garcia-Gonzalo Francesc R FR Seol Allen D AD O'Toole John F JF Held Susanne S Reutter Heiko M HM Lane William S WS Rafiq Muhammad Arshad MA Noor Abdul A Ansar Muhammad M Devi Akella Radha Rama AR Sheffield Val C VC Slusarski Diane C DC Vincent John B JB Doherty Daniel A DA Hildebrandt Friedhelm F Reiter Jeremy F JF Jackson Peter K PK

Cell 20110501 4

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 ...[more]

PMID: 21565611

Similar Datasets

Project description:Nephronophthisis (NPHP) is a ciliopathy in which genetic modifiers may underlie the variable penetrance of clinical features. To identify modifiers, a screen was conducted on C. elegans nphp-4(tm925) mutants. Mutations in ten loci exacerbating nphp-4(tm925) ciliary defects were obtained. Four loci have been identified, three of which are established ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly. While osm-3(yhw66) mutants alone have no overt cilia phenotype, nphp-4(tm925);osm-3(yhw66) double mutants lack distal segments and are dye-filling (Dyf) and osmotic avoidance (Osm) defective, similar to osm-3(mn357) null mutants. In osm-3(yhw66) mutants anterograde intraflagellar transport (IFT) velocity is reduced. Furthermore, expression of OSM-3(S316F)::GFP reduced IFT velocities in nphp-4(tm925) mutants, but not in wild type animals. In silico analysis indicates the S316F mutation may affect a phosphorylation site. Putative phospho-null OSM-3(S316F) and phospho-mimetic OSM-3(S316D) proteins accumulate at the cilia base and tip respectively. FRAP analysis indicates that the cilia entry rate of OSM-3(S316F) is slower than OSM-3 and that in the presence of OSM-3(S316F), OSM-3 and OSM-3(S316D) rates decrease. In the presence OSM-3::GFP or OSM-3(S316D)::GFP, OSM-3(S316F)::tdTomato redistributes along the cilium and accumulates in the cilia tip. OSM-3(S316F) and OSM-3(S316D) are functional as they restore cilia distal segment formation in osm-3(mn357) null mutants; however, only OSM-3(S316F) rescues the osm-3(mn357) null Dyf phenotype. Despite rescue of cilia length in osm-3(mn357) null mutants, neither OSM-3(S316F) nor OSM-3(S316D) restores ciliary defects in nphp-4(tm925);osm-3(yhw66) double mutants. Thus, these OSM-3 mutations cause NPHP-4 dependent and independent phenotypes. These data indicate that in addition to regulating cilia protein entry or exit, NPHP-4 influences localization and function of a distal ciliary kinesin. Moreover, data suggest human OSM-3 homolog (Kif17) could act as a modifying locus affecting disease penetrance or expressivity in NPHP patients.

Project description:Uncovering the dominant molecular deregulation among the multitude of pathways implicated in aggressive prostate cancer is essential to intelligently developing targeted therapies. Paradoxically, published prostate cancer gene expression signatures of poor prognosis share little overlap and thus do not reveal shared mechanisms. The authors hypothesize that, by analyzing gene signatures with quantitative models of protein-protein interactions, key pathways will be elucidated and shown to be shared.The authors statistically prioritized common interactors between established cancer genes and genes from each prostate cancer signature of poor prognosis independently via a previously validated single protein analysis of network (SPAN) methodology. Additionally, they computationally identified pathways among the aggregated interactors across signatures and validated them using a similarity metric and patient survival.Using an information-theoretic metric, the authors assessed the mechanistic similarity of the interactor signature. Its prognostic ability was assessed in an independent cohort of 198 patients with high-Gleason prostate cancer using Kaplan-Meier analysis.Of the 13 prostate cancer signatures that were evaluated, eight interacted significantly with established cancer genes (false discovery rate <5%) and generated a 42-gene interactor signature that showed the highest mechanistic similarity (p<0.0001). Via parameter-free unsupervised classification, the interactor signature dichotomized the independent prostate cancer cohort with a significant survival difference (p=0.009). Interpretation of the network not only recapitulated phosphatidylinositol-3 kinase/NF-?B signaling, but also highlighted less well established relevant pathways such as the Janus kinase 2 cascade.SPAN methodology provides a robust means of abstracting disparate prostate cancer gene expression signatures into clinically useful, prioritized pathways as well as useful mechanistic pathways.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets