title: 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.
authors.affiliation: Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Liyun
authors.initials: L
authors.lastname: Sang
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Miller
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Corbit
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brauer
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Baye
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wen
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.forename: Mandy
authors.initials: M
authors.lastname: Kwong
authors.forename: Erik G
authors.initials: EG
authors.lastname: Huntzicker
authors.forename: Mindan K
authors.initials: MK
authors.lastname: Sfakianos
authors.forename: Wendy
authors.initials: W
authors.lastname: Sandoval
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Priya
authors.initials: P
authors.lastname: Kulkarni
authors.forename: Francesc R
authors.initials: FR
authors.lastname: Garcia-Gonzalo
authors.forename: Allen D
authors.initials: AD
authors.lastname: Seol
authors.forename: John F
authors.initials: JF
authors.lastname: O'Toole
authors.forename: Susanne
authors.initials: S
authors.lastname: Held
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Akella Radha Rama
authors.initials: AR
authors.lastname: Devi
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Diane C
authors.initials: DC
authors.lastname: Slusarski
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Doherty
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
mesh_terms: D000818:Animals; D000067736:Ataxin-10; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D002925:Ciliary Motility Disorders / Q000235:genetics; D004677:Encephalocele / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics; D007690:Polycystic Kidney Diseases / Q000235:genetics; D012174:Retinitis Pigmentosa; D015398:Signal Transduction; D015027:Zebrafish
chemical_list: C503889:ATXN10 protein, human; D000067736:Ataxin-10; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C111171:tectonin II