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

L. Sang; J.J. Miller; K. Corbit; R.H. Giles; M.J. Brauer; E.A. Otto; L.M. Baye; X. Wen; S.J. Scales; M. Kwong; E. Huntzicker; M. Sfakianos; W. Sandoval; J.F. Bazan; M.A. Kulkarni; A Noor; M. Ansar; A. Devi; V. Sheffield; D. Slusarski; J.B. Vincent; D. Doherty; F. Hildebrandt; J.F. Reiter; P.K. Jackson

doi:10.1016/j.cell.2011.04.019

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

L. Sang, J.J. Miller, K. Corbit, R.H. Giles, M.J. Brauer, E.A. Otto, L.M. Baye, X. Wen, S.J. Scales, M. Kwong, E. Huntzicker, M. Sfakianos, W. Sandoval, J.F. Bazan, M.A. Kulkarni, A Noor, M. Ansar, A. Devi, V. Sheffield, D. SlusarskiJ.B. Vincent, D. Doherty, F. Hildebrandt, J.F. Reiter, P.K. Jackson

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	513-528
Number of pages	16
Journal	Cell
Volume	145
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2011.04.019
Publication status	Published - 2011

Keywords

Animals
Ataxin-10
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

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10.1016/j.cell.2011.04.019

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Sang, L., Miller, J. J., Corbit, K., Giles, R. H., Brauer, M. J., Otto, E. A., Baye, L. M., Wen, X., Scales, S. J., Kwong, M., Huntzicker, E., Sfakianos, M., Sandoval, W., Bazan, J. F., Kulkarni, M. A., Noor, A., Ansar, M., Devi, A., Sheffield, V., ... Jackson, P. K. (2011). Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell, 145(4), 513-528. https://doi.org/10.1016/j.cell.2011.04.019

@article{aae40f3b32624ef291fcd90428738d2e,

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.",

keywords = "Animals, Ataxin-10, 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",

author = "L. Sang and J.J. Miller and K. Corbit and R.H. Giles and M.J. Brauer and E.A. Otto and L.M. Baye and X. Wen and S.J. Scales and M. Kwong and E. Huntzicker and M. Sfakianos and W. Sandoval and J.F. Bazan and M.A. Kulkarni and A Noor and M. Ansar and A. Devi and V. Sheffield and D. Slusarski and J.B. Vincent and D. Doherty and F. Hildebrandt and J.F. Reiter and P.K. Jackson",

year = "2011",

doi = "10.1016/j.cell.2011.04.019",

language = "English",

volume = "145",

pages = "513--528",

number = "4",

}

Sang, L, Miller, JJ, Corbit, K, Giles, RH, Brauer, MJ, Otto, EA, Baye, LM, Wen, X, Scales, SJ, Kwong, M, Huntzicker, E, Sfakianos, M, Sandoval, W, Bazan, JF, Kulkarni, MA, Noor, A, Ansar, M, Devi, A, Sheffield, V, Slusarski, D, Vincent, JB, Doherty, D, Hildebrandt, F, Reiter, JF & Jackson, PK 2011, 'Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways', Cell, vol. 145, no. 4, pp. 513-528. https://doi.org/10.1016/j.cell.2011.04.019

TY - JOUR

T1 - Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways

AU - Sang, L.

AU - Miller, J.J.

AU - Corbit, K.

AU - Giles, R.H.

AU - Brauer, M.J.

AU - Otto, E.A.

AU - Baye, L.M.

AU - Wen, X.

AU - Scales, S.J.

AU - Kwong, M.

AU - Huntzicker, E.

AU - Sfakianos, M.

AU - Sandoval, W.

AU - Bazan, J.F.

AU - Kulkarni, M.A.

AU - Noor, A

AU - Ansar, M.

AU - Devi, A.

AU - Sheffield, V.

AU - Slusarski, D.

AU - Vincent, J.B.

AU - Doherty, D.

AU - Hildebrandt, F.

AU - Reiter, J.F.

AU - Jackson, P.K.

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Animals

KW - Ataxin-10

KW - Centrosome

KW - Cilia

KW - Ciliary Motility Disorders

KW - Encephalocele

KW - Hedgehog Proteins

KW - Humans

KW - Kidney Diseases, Cystic

KW - Membrane Proteins

KW - Mice

KW - NIH 3T3 Cells

KW - Nerve Tissue Proteins

KW - Polycystic Kidney Diseases

KW - Signal Transduction

KW - Zebrafish

U2 - 10.1016/j.cell.2011.04.019

DO - 10.1016/j.cell.2011.04.019

M3 - Article

C2 - 21565611

SN - 0092-8674

VL - 145

SP - 513

EP - 528

JO - Cell

JF - Cell

IS - 4

ER -

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

Abstract

Keywords

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