De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

被引：44

作者：

Manole, Andreea ^{[1
]}

Efthymiou, Stephanie ^{[1
]}

O'Connor, Emer ^{[1
]}

Mendes, Marisa, I ^{[2
]}

Jennings, Matthew ^{[3
]}

Maroofian, Reza ^{[1
]}

Davagnanam, Indran ^{[49
]}

Mankad, Kshitij ^{[4
]}

Lopez, Maria Rodriguez ^{[5
]}

Salpietro, Vincenzo ^{[1
]}

Harripaul, Ricardo ^{[6
,7
,8
]}

Badalato, Lauren ^{[9
]}

Walia, Jagdeep ^{[9
]}

Francklyn, Christopher S. ^{[10
]}

Athanasiou-Fragkouli, Alkyoni ^{[1
]}

Sullivan, Roisin ^{[1
]}

Desai, Sonal ^{[11
]}

Baranano, Kristin ^{[11
]}

Zafar, Faisal ^{[12
]}

Rana, Nuzhat ^{[12
]}

Ilyas, Muhammed ^{[13
]}

Horga, Alejandro ^{[1
]}

Kara, Majdi ^{[14
]}

Mattioli, Francesca ^{[17
]}

Goldenberg, Alice ^{[16
]}

Griffin, Helen ^{[3
]}

Piton, Amelie ^{[17
]}

Henderson, Lindsay B. ^{[18
]}

Kara, Benyekhlef ^{[19
]}

Aslanger, Ayca Dilruba ^{[19
]}

Raaphorst, Joost ^{[20
,21
]}

Pfundt, Rolph ^{[20
]}

Portier, Ruben ^{[22
]}

Shinawi, Marwan ^{[23
]}

Kirby, Amelia ^{[24
]}

Christensen, Katherine M. ^{[24
]}

Wang, Lu ^{[25
,26
]}

Rosti, Rasim O. ^{[25
,26
]}

Paracha, Sohail A. ^{[27
]}

Sarwar, Muhammad T. ^{[27
]}

Jenkins, Dagan ^{[51
,52
]}

Ahmed, Jawad ^{[27
]}

Santoni, Federico A. ^{[28
,29
]}

Ranza, Emmanuelle ^{[28
,30
,31
]}

Iwaszkiewicz, Justyna ^{[32
]}

Cytrynbaum, Cheryl ^{[33
]}

Weksberg, Rosanna ^{[33
]}

Wentzensen, Ingrid M. ^{[18
]}

Sacoto, Maria J. Guillen ^{[18
]}

Si, Yue ^{[18
]}

机构：

[1] Univ Coll London UCL, Dept Neuromuscular Disorders, Inst Neurol, Queen Sq, London WC1N 3BG, England

[2] Vrije Univ Amsterdam, Amsterdam Univ Med Ctr, Dept Clin Chem, Metab Unit,Amsterdam Neurosci,Amsterdam Gastroent, NL-1081 Amsterdam, Netherlands

[3] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0QQ, England

[4] Great Ormond St Hosp Sick Children, Dept Neuroradiol, London WC1N 3JH, England

[5] Univ Coll London UCL, Inst Hlth Ageing, Dept Genet Evolut & Environm, London WC1E 6BT, England

[6] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Toronto, ON M5T 1R8, Canada

[7] Univ Toronto, Inst Med Sci, Toronto, ON M5T 1R8, Canada

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

[9] Queens Univ, Dept Pediat, Kingston, ON K7L 2V7, Canada

[10] Univ Vermont, Dept Biochem, Coll Med, Burlington, VT 05405 USA

[11] Johns Hopkins Sch Med, Dept Neurol & Pediat, Baltimore, MD 21205 USA

[12] Multan Hosp, Dept Pediat, Multan 60000, Pakistan

[13] Univ Islamabad, Islamabad 45320, Pakistan

[14] Tripoli Childrens Hosp, Dept Pediat, Tripoli, Libya

[15] Univ Strasbourg, CNRS, GMGM, UMR 7156, F-67083 Strasbourg, France

[16] Normandie Univ, Ctr Reference Anomalies Dev & Syndromes Malformat, Ctr Normand Genom & Med Personnalisee, Dept Genet,CHU Rouen,Inserm U1245,UNIROUEN, F-76031 Rouen, France

[17] Univ Strasbourg, Inst Genet & Mol & Cellular Biol IGBMC, INSERM U1258, CNRS,UMR7104, F-67404 Illkirch Graffenstaden, France

[18] GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA

[19] Bezmialem Vakif Univ, TR-34093 Istanbul, Turkey

[20] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Human Genet, Med Ctr, NL-6500 HB Nijmegen, Netherlands

[21] Univ Amsterdam, Amsterdam Neurosci Inst, Dept Neurol, Med Ctr, NL-1105 AZ Amsterdam, Netherlands

[22] Med Spectrum Twente, Dept Neurol, NL-7512 KZ Enschede, Netherlands

[23] Washington Univ, Dept Pediat, Div Genet & Genom Med, Sch Med, St Louis, MO 63110 USA

[24] St Louis Univ, SSM Hlth Cardinal Glennon Childrens Hosp, Div Med Genet, Sch Med, St Louis, MO 63104 USA

[25] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92130 USA

[26] Rady Childrens Hosp, La Jolla, CA 92130 USA

[27] Khyber Med Univ, Inst Basic Med Sci, Peshawar 25100, Pakistan

[28] Univ Geneva, Dept Genet Med & Dev, CH-1206 Geneva, Switzerland

[29] Univ Hosp Lausanne, Dept Endocrinol Diabet & Metab, CH-1011 Lausanne, Switzerland

[30] Univ Hosp Geneva, Serv Genet Med, CH-1205 Geneva, Switzerland

[31] Swiss Inst Genom Med, Medigenome, CH-1207 Geneva, Switzerland

[32] Swiss Inst Bioinformat, Unil Sorge, Mol Modeling Grp, Batiment Genopode, CH-1015 Lausanne, Switzerland

[33] Hosp Sick Children, Div Clin & Metab Genet, 555 Univ Ave, Toronto, ON M5G 1X8, Canada

[34] CeGaT GmbH, D-72076 Tubingen, Germany

[35] Praxis Humangenet Tuebingen, D-72076 Tubingen, Germany

[36] Biomed Ctr Cardinal, Wendel Str 14, D-66424 Hamburg, Germany

[37] Univ Groningen, Univ Med Ctr Groningen, Dept Neurol, NL-9713 Groningen, Netherlands

[38] Maastricht Univ, Dept Clin Genet, Med Ctr, NL-6211 Maastricht, Netherlands

[39] Univ Hlth Sci, Allama Iqbal Med Coll, Jinnah Burn & Reconstruct Surg Ctr, Lahore 54550, Pakistan

[40] Heinrich Heine Univ, Dept Gen Pediat, Moorenstr 5, D-40225 Dusseldorf, Germany

[41] iGE3 Inst Genet & Genom Geneva, CH-1211 Geneva, Switzerland

[42] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany

[43] Univ Hosp Copenhagen, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark

[44] West Virginia Univ, Dept Pediat, Sect Med Genet, Morgantown, WV 26506 USA

[45] Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany

[46] St Georges Univ London, Genet Ctr, Mol & Clin Sci Inst, London SW17 0RE, England

[47] Washington Univ, Div Child Neurol, Sch Med, St Louis, MO 63110 USA

[48] Johns Hopkins Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA

[49] UCL Inst Neurol, Dept Brain Repair & Rehabil, Queen Sq, London WC1N 3BG, England

[50] Inst Mol & Clin Ophthalmol Basel, Basel, Switzerland

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2020年 / 107卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

TRANSFER-RNA SYNTHETASE; 2; SIBLINGS; MUTATIONS; EXPRESSION;

D O I：

10.1016/j.ajhg.2020.06.016

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

引用

页码：311 / 324

页数：14

共 44 条

[1] HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].

Anders, Simon ;

Pyl, Paul Theodor ;

Huber, Wolfgang .

BIOINFORMATICS, 2015, 31 (02) :166-169

[2] The role of aminoacyl-tRNA synthetases in genetic diseases [J].

Antonellis, Anthony ;

Green, Eric D. .

ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, 2008, 9 :87-107

[3] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[4]

Bähler J, 1998, YEAST, V14, P943, DOI 10.1002/(SICI)1097-0061(199807)14:10<943::AID-YEA292>3.0.CO

[5]

2-Y

[6] Mutations in the pre-replication complex cause Meier-Gorlin syndrome [J].

Bicknell, Louise S. ;

Bongers, Ernie M. H. F. ;

Leitch, Andrea ;

Brown, Stephen ;

Schoots, Jeroen ;

Harley, Margaret E. ;

Aftimos, Salim ;

Al-Aama, Jumana Y. ;

Bober, Michael ;

Brown, Paul A. J. ;

van Bokhoven, Hans ;

Dean, John ;

Edrees, Alaa Y. ;

Feingold, Murray ;

Fryer, Alan ;

Hoefsloot, Lies H. ;

Kau, Nikolaus ;

Knoers, Nine V. A. M. ;

MacKenzie, James ;

Opitz, John M. ;

Sarda, Pierre ;

Ross, Alison ;

Temple, I. Karen ;

Toutain, Annick ;

Wise, Carol A. ;

Wright, Michael ;

Jackson, Andrew P. .

NATURE GENETICS, 2011, 43 (04) :356-+

[7] Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons [J].

Boczonadi, Veronika ;

Meyer, Kathrin ;

Gonczarowska-Jorge, Humberto ;

Griffin, Helen ;

Roos, Andreas ;

Bartsakoulia, Marina ;

Bansagi, Boglarka ;

Ricci, Giulia ;

Palinkas, Fanni ;

Zahedi, Rene P. ;

Bruni, Francesco ;

Kaspar, Brian ;

Lochmueller, Hanns ;

Boycott, Kym M. ;

Mueller, Juliane S. ;

Horvath, Rita .

HUMAN MOLECULAR GENETICS, 2018, 27 (12) :2187-2204

[8] The role of tRNA synthetases in neurological and neuromuscular disorders [J].

Boczonadi, Veronika ;

Jennings, Matthew J. ;

Horvath, Rita .

FEBS LETTERS, 2018, 592 (05) :703-717

[9] Distribution and intensity of constraint in mammalian genomic sequence [J].

Cooper, GM ;

Stone, EA ;

Asimenos, G ;

Green, ED ;

Batzoglou, S ;

Sidow, A .

GENOME RESEARCH, 2005, 15 (07) :901-913

[10] Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-Binding domain [J].

Dong, JS ;

Qiu, HF ;

Garcia-Barrio, M ;

Anderson, J ;

Hinnebusch, AG .

MOLECULAR CELL, 2000, 6 (02) :269-279

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