TY  - JOUR
AU  - Boldt, Karsten
AU  - van Reeuwijk, Jeroen
AU  - Lu, Qianhao
AU  - Koutroumpas, Konstantinos
AU  - Nguyen, Thanh-Minh T
AU  - Texier, Yves
AU  - van Beersum, Sylvia E C
AU  - Horn, Nicola
AU  - Willer, Jason R
AU  - Mans, Dorus A
AU  - Dougherty, Gerard
AU  - Lamers, Ideke J C
AU  - Coene, Karlien L M
AU  - Arts, Heleen H
AU  - Betts, Matthew J
AU  - Beyer, Tina
AU  - Bolat, Emine
AU  - Gloeckner, Christian Johannes
AU  - Haidari, Khatera
AU  - Hetterschijt, Lisette
AU  - Iaconis, Daniela
AU  - Jenkins, Dagan
AU  - Klose, Franziska
AU  - Knapp, Barbara
AU  - Latour, Brooke
AU  - Letteboer, Stef J F
AU  - Marcelis, Carlo L
AU  - Mitic, Dragana
AU  - Morleo, Manuela
AU  - Oud, Machteld M
AU  - Riemersma, Moniek
AU  - Rix, Susan
AU  - Terhal, Paulien A
AU  - Toedt, Grischa
AU  - van Dam, Teunis J P
AU  - de Vrieze, Erik
AU  - Wissinger, Yasmin
AU  - Wu, Ka Man
AU  - Apic, Gordana
AU  - Beales, Philip L
AU  - Blacque, Oliver E
AU  - Gibson, Toby J
AU  - Huynen, Martijn A
AU  - Katsanis, Nicholas
AU  - Kremer, Hannie
AU  - Omran, Heymut
AU  - van Wijk, Erwin
AU  - Wolfrum, Uwe
AU  - Kepes, François
AU  - Davis, Erica E
AU  - Franco, Brunella
AU  - Giles, Rachel H
AU  - Ueffing, Marius
AU  - Russell, Robert B
AU  - Roepman, Ronald
AU  - Group, UK10K Rare Diseases
AU  - Al-Turki, Saeed
AU  - Anderson, Carl
AU  - Antony, Dinu
AU  - Barroso, Inês
AU  - Bentham, Jamie
AU  - Bhattacharya, Shoumo
AU  - Carss, Keren
AU  - Chatterjee, Krishna
AU  - Cirak, Sebahattin
AU  - Cosgrove, Catherine
AU  - Danecek, Petr
AU  - Durbin, Richard
AU  - Fitzpatrick, David
AU  - Floyd, Jamie
AU  - Reghan Foley, A.
AU  - Franklin, Chris
AU  - Futema, Marta
AU  - Humphries, Steve E
AU  - Hurles, Matt
AU  - Joyce, Chris
AU  - McCarthy, Shane
AU  - Mitchison, Hannah M
AU  - Muddyman, Dawn
AU  - Muntoni, Francesco
AU  - O'Rahilly, Stephen
AU  - Onoufriadis, Alexandros
AU  - Payne, Felicity
AU  - Plagnol, Vincent
AU  - Raymond, Lucy
AU  - Savage, David B
AU  - Scambler, Peter
AU  - Schmidts, Miriam
AU  - Schoenmakers, Nadia
AU  - Semple, Robert
AU  - Serra, Eva
AU  - Stalker, Jim
AU  - van Kogelenberg, Margriet
AU  - Vijayarangakannan, Parthiban
AU  - Walter, Klaudia
AU  - Whittall, Ros
AU  - Williamson, Kathy
TI  - An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
JO  - Nature Communications
VL  - 7
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-04883
SP  - 11491
PY  - 2016
AB  - Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
KW  - Biological Transport: physiology
KW  - Chromatography, Affinity: methods
KW  - Cilia: metabolism
KW  - Ciliopathies: genetics
KW  - Ciliopathies: pathology
KW  - Ciliopathies: therapy
KW  - DNA Mutational Analysis
KW  - Datasets as Topic
KW  - Dwarfism: genetics
KW  - Dwarfism: pathology
KW  - Dwarfism: therapy
KW  - Fibroblasts
KW  - HEK293 Cells
KW  - Humans
KW  - Mass Spectrometry
KW  - Molecular Targeted Therapy: methods
KW  - Muscle Hypotonia: genetics
KW  - Muscle Hypotonia: pathology
KW  - Muscle Hypotonia: therapy
KW  - Protein Interaction Mapping: methods
KW  - Protein Interaction Maps
KW  - Proteins: genetics
KW  - Proteins: isolation & purification
KW  - Proteins: metabolism
KW  - Proteomics: methods
KW  - Spine: abnormalities
KW  - Spine: pathology
KW  - Systems Analysis
KW  - Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27173435
C2  - pmc:PMC4869170
DO  - DOI:10.1038/ncomms11491
UR  - https://pub.dzne.de/record/138561
ER  -