Journal article
Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways
Cell (Cambridge), Vol.145(4), pp.513-528
05/13/2011
DOI: 10.1016/j.cell.2011.04.019
PMCID: PMC3383065
PMID: 21565611
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.
Details
- Title: Subtitle
- Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways
- Creators
- Liyun Sang - Genentech Inc., South San Francisco, CA 94080, USAJulie J MillerKevin C CorbitRachel H GilesMatthew J BrauerEdgar A OttoLisa M BayeXiaohui WenSuzie J ScalesMandy KwongErik G HuntzickerMindan K SfakianosWendy SandovalJ Fernando BazanPriya KulkarniFrancesc R Garcia-GonzaloAllen D SeolJohn F O'TooleSusanne HeldHeiko M ReutterWilliam S LaneMuhammad Arshad RafiqAbdul NoorMuhammad AnsarAkella Radha Rama DeviVal C SheffieldDiane C SlusarskiJohn B VincentDaniel A DohertyFriedhelm HildebrandtJeremy F ReiterPeter K Jackson
- Resource Type
- Journal article
- Publication Details
- Cell (Cambridge), Vol.145(4), pp.513-528
- DOI
- 10.1016/j.cell.2011.04.019
- PMID
- 21565611
- PMCID
- PMC3383065
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- United States
- Grant note
- K08 DK071108 / NIDDK NIH HHS R01 DK068306 / NIDDK NIH HHS Howard Hughes Medical Institute CA112369 / NCI NIH HHS K08 DK071108-01A1 / NIDDK NIH HHS R01 GM095941-01A1 / NIGMS NIH HHS KL2RR025015 / NCRR NIH HHS MOP-102758 / Canadian Institutes of Health Research R01-EY11298 / NEI NIH HHS R01 CA112369 / NCI NIH HHS DK090917 / NIDDK NIH HHS R01-EY017168 / NEI NIH HHS KL2 RR025015 / NCRR NIH HHS R01 EY017168-01A2 / NEI NIH HHS R01 GM095941 / NIGMS NIH HHS RC4 DK090917-01 / NIDDK NIH HHS RC4 DK090917 / NIDDK NIH HHS R01 EY011298 / NEI NIH HHS T32 GM007365 / NIGMS NIH HHS R01 AR054396 / NIAMS NIH HHS R01 NS064077-01A2 / NINDS NIH HHS R01-AR054396 / NIAMS NIH HHS R01 EY011298-04 / NEI NIH HHS R01 NS064077 / NINDS NIH HHS R01 CA112369-01 / NCI NIH HHS GM07365-33 / NIGMS NIH HHS DK071108 / NIDDK NIH HHS T32 HL007121 / NHLBI NIH HHS R01 AR054396-01A1 / NIAMS NIH HHS R01 EY017168 / NEI NIH HHS DK1069274 / NIDDK NIH HHS DK1068306 / NIDDK NIH HHS R01NS064077 / NINDS NIH HHS
- Language
- English
- Date published
- 05/13/2011
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Ophthalmology and Visual Sciences
- Record Identifier
- 9983980070602771
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