Mapping the NPHP-JBTS-MKS Protein Network Reveals Ciliopathy Disease Genes and Pathways

被引：459

作者：

Sang, Liyun ^{[1
]}

Miller, Julie J. ^{[2
]}

Corbit, Kevin C. ^{[3
]}

Giles, Rachel H. ^{[4
,5
]}

Brauer, Matthew J. ^{[1
]}

Otto, Edgar A. ^{[6
,7
]}

Baye, Lisa M. ^{[8
]}

Wen, Xiaohui ^{[1
]}

Scales, Suzie J. ^{[1
]}

Kwong, Mandy ^{[1
]}

Huntzicker, Erik G. ^{[1
]}

Sfakianos, Mindan K. ^{[1
]}

Sandoval, Wendy ^{[1
]}

Bazan, J. Fernando ^{[1
]}

Kulkarni, Priya ^{[1
]}

Garcia-Gonzalo, Francesc R. ^{[3
]}

Seol, Allen D. ^{[3
]}

O'Toole, John F. ^{[6
,7
]}

Held, Susanne ^{[6
,7
]}

Reutter, Heiko M. ^{[10
,11
]}

Lane, William S. ^{[12
]}

Rafiq, Muhammad Arshad ^{[13
]}

Noor, Abdul ^{[13
]}

Ansar, Muhammad ^{[14
]}

Devi, Akella Radha Rama ^{[15
]}

Sheffield, Val C. ^{[9
,18
]}

Slusarski, Diane C. ^{[8
]}

Vincent, John B. ^{[13
,16
]}

Doherty, Daniel A. ^{[17
]}

Hildebrandt, Friedhelm ^{[6
,7
,18
]}

Reiter, Jeremy F. ^{[3
]}

Jackson, Peter K. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 USA

[3] Univ Calif San Francisco, Dept Biochem & Biophys, Cardiovasc Res Inst, San Francisco, CA 94158 USA

[4] Univ Med Ctr Utrecht, Dept Med Oncol, NL-3584 CX Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Dept Hypertens & Nephrol, NL-3584 CX Utrecht, Netherlands

[6] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[8] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA

[9] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA

[10] Univ Bonn, Childrens Hosp, Inst Human Genet, D-53111 Bonn, Germany

[11] Univ Bonn, Childrens Hosp, Dept Neonatol, D-53111 Bonn, Germany

[12] Harvard Univ, Mass Spectrometry & Prote Resource Lab, Ctr Syst Biol, Cambridge, MA 02138 USA

[13] Ctr Addict & Mental Hlth, Mol Neuropsychiat & Dev Lab, Neurogenet Sect, Toronto, ON M5T 1R8, Canada

[14] Quaid i Azam Univ, Dept Biochem, Islamabad 45320, Pakistan

[15] Rainbow Childrens Hosp, Hyderabad 500034, Andhra Pradesh, India

[16] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada

[17] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[18] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2011年 / 145卷 / 04期

基金：

加拿大健康研究院;

关键词：

MECKEL-SYNDROME; PRIMARY CILIA; TRANSITION ZONE; INTRAFLAGELLAR TRANSPORT; RETINAL DEGENERATION; KIDNEY-DISEASE; NEPHRONOPHTHISIS; NEPHROCYSTIN; MOUSE; CILIOGENESIS;

D O I：

10.1016/j.cell.2011.04.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：513 / 528

页数：16

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