Brain malformations and seizures by impaired chaperonin function of TRiC

被引：1

作者：

Kraft, Florian ^{[1
]}

Rodriguez-Aliaga, Piere ^{[2
]}

Yuan, Weimin ^{[3
]}

Franken, Lena ^{[1
]}

Zajt, Kamil ^{[4
]}

Hasan, Dimah ^{[5
]}

Lee, Ting-Ting ^{[2
]}

Flex, Elisabetta ^{[6
]}

Hentschel, Andreas ^{[7
]}

Innes, A. Micheil ^{[8
,9
]}

Zheng, Bixia ^{[10
]}

Suh, Dong Sun Julia ^{[1
]}

Knopp, Cordula ^{[1
]}

Lausberg, Eva ^{[1
]}

Krause, Jeremias ^{[1
]}

Zhang, Xiaomeng ^{[4
]}

Trapane, Pamela ^{[11
]}

Carroll, Riley ^{[11
]}

Mcclatchey, Martin ^{[12
,13
]}

Fry, Andrew E. ^{[13
,14
]}

Wang, Lisa ^{[4
]}

Giesselmann, Sebastian ^{[1
]}

Hoang, Hieu ^{[3
]}

Baldridge, Dustin ^{[3
]}

Silverman, Gary A. ^{[3
]}

Radio, Francesca Clementina ^{[15
]}

Bertini, Enrico ^{[16
]}

Ciolfi, Andrea ^{[15
]}

Blood, Katherine A. ^{[17
]}

Agathe, Jean-Madeleine de Sainte ^{[18
,19
]}

Charles, Perrine ^{[18
]}

Bergant, Gaber ^{[20
]}

Cuturilo, Goran ^{[21
,22
]}

Peterlin, Borut ^{[20
]}

Diderich, Karin ^{[23
]}

Streff, Haley ^{[24
]}

Robak, Laurie ^{[24
]}

Oegema, Renske ^{[25
]}

van Binsbergen, Ellen ^{[25
]}

Herriges, John ^{[26
,27
]}

Saunders, Carol J. ^{[26
,27
,28
]}

Maier, Andrea ^{[29
,30
]}

Wolking, Stefan ^{[31
]}

Weber, Yvonne ^{[31
]}

Lochmuller, Hanns ^{[32
,33
]}

Meyer, Stefanie ^{[32
,33
]}

Aleman, Alberto ^{[32
,33
]}

Polavarapu, Kiran ^{[32
,33
,34
]}

Nicolas, Gael ^{[35
,36
,37
]}

Goldenberg, Alice ^{[35
,36
]}

机构：

[1] Univ Aachen RWTH, Dept Nucl Med, Fac Med, D-52074 Aachen, Germany

[2] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[3] Washington Univ St Louis, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[4] RWTH Aachen Univ Hosp, Inst Neuropathol, D-52074 Aachen, Germany

[5] RWTH Aachen Univ Hosp, Dept Diagnost & Intervent Neuroradiol, Aachen, Germany

[6] Ist Super San, Dept Oncol & Mol Med, I-00161 Rome, Italy

[7] Leibniz Inst Analyt Wissensch ISAS eV, D-44139 Dortmund, Germany

[8] Univ Calgary, Dept Med Genet, Calgary, AB T2N 1N4, Canada

[9] Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB T2N 1N4, Canada

[10] Nanjing Med Univ, Childrens Hosp, Nanjing Key Lab Pediat, Nanjing 210008, Peoples R China

[11] Univ Florida, Div Neonatol, Coll Med Jacksonville, Dept Pediat, Jacksonville, FL 32209 USA

[12] Univ Wales Hosp, Inst Med Genet, Cardiff CF14 4XW, Wales

[13] Cardiff Univ, Div Canc & Genet, Heath Pk, Cardiff CF14 4XN, Wales

[14] Univ Hosp Wales, All Wales Med Genom Lab, Heath Pk, Cardiff CF14 4XW, Wales

[15] IRCCS, Osped Pediatr Bambino Gesu, Mol Genet & Funct Genom, Rome, Italy

[16] IRCCS, Osped Pediatr Bambino Gesu, Neuromuscular Disorders, I-00146 Rome, Italy

[17] UNIV BRITISH COLUMBIA, DEPT MED GENET, VANCOUVER, BC V6T 2A1, Canada

[18] Sorbonne Univ, Pitie Salpetriere Univ Hosp, AP HP, AP HP, Paris, France

[19] Sorbonne Univ, LBM SeqOIA, Lab Medecine Genomique, F-75014 Paris, France

[20] Univ Med Ctr Ljubljana, Clin Inst Genom Med, Ljubljana 1000, Slovenia

[21] Univ Belgrade, Fac Med, Belgrade 11000, Serbia

[22] Univ Childrens Hosp, Belgrade 11000, Serbia

[23] Erasmus MC, Dept Clin Genet, NL-3015 GD Rotterdam, Netherlands

[24] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[25] Univ Utrecht, Univ Med Ctr Utrecht, Dept Genet, NL-3584 CX Utrecht, Netherlands

[26] Childrens Mercy Kansas City, Dept Pathol & Lab Med, Kansas City, MO 64108 USA

[27] Univ Missouri, Kansas City Sch Med, Kansas City, MO 64108 USA

[28] Childrens Mercy Res Inst, Genom Med Ctr, Kansas City, MO 64108 USA

[29] Rhein Westfal TH Aachen, Univ Hosp, D-52074 Aachen, Germany

[30] Univ Hosp RWTH Aachen, Ctr Rare Dis Aachen ZSEA, Aachen, Germany

[31] Univ Aachen RWTH, Dept Radiol, Fac Med, D-52074 Aachen, Germany

[32] Ottawa Hosp, Eastern Ontario Res Inst, Childrens Hosp, Div Neurol,Dept Med, Ottawa, ON K1H 8L1, Canada

[33] Univ Ottawa, Brain & Mind Res Inst, Ottawa, ON K1H 8L1, Canada

[34] Natl Inst Mental Hlth & Neuro Sci NIMHANS, Dept Neurol, Bangalore, India

[35] Normandie univ, Univ Rouen Normandie, Inserm U1245, F-76000 Rouen, France

[36] CHU Rouen, Reference Ctr Neurogenet Diorders, Dept Genet, F-76000 Rouen, France

[37] Lab Multisites SeqOIA, F-75014 Paris, France

[38] Univ S Florida, Coll Publ Hlth, Tampa, FL 33612 USA

[39] Nemours Childrens Hlth, Dept Pediat, Div Genet, Orlando, FL 32827 USA

[40] GeneDx, Gaithersburg, MD 20877 USA

[41] RWTH Aachen Univ Hosp, Dept Pediat, Div Pediat Neurol & Social Pediat, Aachen, Germany

[42] CHU Lille, Lille Univ Hosp, Dept Clin Genet, F-59000 Lille, France

[43] Univ Libre Bruxelles, Hop Erasme, Dept Pediat Neurol, B-1070 Brussels, Belgium

[44] UNIV LIBRE BRUXELLES, HOP ERASME,DEPT NEUROL, B-1070 BRUSSELS, Belgium

[45] Katholieke Univ Leuven, Lab Epilepsy Res, B-3000 Louvain, Belgium

[46] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium

[47] Hosp Valais, Cent Inst Hosp, Serv Clin Chem & Toxicol, Sion, Switzerland

[48] Univ Hosp Geneva, Dept Genet Med, CH-1205 Geneva, Switzerland

[49] Univ Geneva, Med Fac, CH-1205 Geneva, Switzerland

[50] Cent Inst Hosp, Valais Hosp, Div Med Genet, CH-1951 Sion, Switzerland

来源：

SCIENCE | 2024年 / 386卷 / 6721期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

CAENORHABDITIS-ELEGANS CHAPERONIN; DE-NOVO MUTATIONS; EUKARYOTIC CHAPERONIN; CORTICAL DEVELOPMENT; NEURONAL MIGRATION; TUBULIN; SUBUNIT; GENES; INTERACTOME; ZEBRAFISH;

D O I：

10.1126/science.adp8721

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Malformations of the brain are common and vary in severity, from negligible to potentially fatal. Their causes have not been fully elucidated. Here, we report pathogenic variants in the core protein-folding machinery TRiC/CCT in individuals with brain malformations, intellectual disability, and seizures. The chaperonin TRiC is an obligate hetero-oligomer, and we identify variants in seven of its eight subunits, all of which impair function or assembly through different mechanisms. Transcriptome and proteome analyses of patient-derived fibroblasts demonstrate the various consequences of TRiC impairment. The results reveal an unexpected and potentially widespread role for protein folding in the development of the central nervous system and define a disease spectrum of "TRiCopathies."

引用

页码：516 / 525

页数：10

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