Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

被引：485

作者：

Rice, Gillian I. ^{[1
]}

Duany, Yoandris del Toro ^{[2
,3
]}

Jenkinson, Emma M. ^{[1
]}

Forte, Gabriella M. A. ^{[1
]}

Anderson, Beverley H. ^{[1
]}

Ariaudo, Giada ^{[4
,5
]}

Bader-Meunier, Brigitte ^{[6
]}

Baildam, Eileen M. ^{[7
]}

Battini, Roberta ^{[8
]}

Beresford, Michael W. ^{[7
,9
]}

Casarano, Manuela ^{[8
]}

Chouchane, Mondher ^{[10
]}

Cimaz, Rolando ^{[11
,12
]}

Collins, Abigail E. ^{[13
]}

Cordeiro, Nuno J. V. ^{[14
]}

Dale, Russell C. ^{[15
]}

Davidson, Joyce E. ^{[16
]}

De Waele, Liesbeth ^{[17
]}

Desguerre, Isabelle ^{[18
]}

Faivre, Laurence ^{[19
,20
]}

Fazzi, Elisa ^{[21
]}

Isidor, Bertrand ^{[22
,23
]}

Lagae, Lieven ^{[17
]}

Latchman, Andrew R. ^{[24
]}

Lebon, Pierre ^{[25
]}

Li, Chumei ^{[26
]}

Livingston, John H. ^{[27
]}

Lourenco, Charles M. ^{[28
]}

Mancardi, Maria Margherita ^{[29
]}

Masurel-Paulet, Alice ^{[19
,20
]}

McInnes, Lain B. ^{[30
]}

Menezes, Manoj P. ^{[31
]}

Mignot, Cyril ^{[32
]}

O'Sullivan, James ^{[1
]}

Orcesi, Simona ^{[4
]}

Picco, Paolo P. ^{[33
]}

Riva, Enrica

Robinson, Robert A. ^{[35
]}

Rodriguez, Diana ^{[36
,37
,38
]}

Salvatici, Elisabetta ^{[34
]}

Scott, Christiaan ^{[39
]}

Szybowska, Marta ^{[26
]}

Tolmie, John L. ^{[40
]}

Vanderver, Adeline ^{[41
]}

Vanhulle, Catherine ^{[42
]}

Vieira, Jose Pedro ^{[43
]}

Webb, Kate ^{[39
]}

Whitney, Robyn N. ^{[44
]}

Williams, Simon G. ^{[1
]}

Wolfe, Lynne A. ^{[45
]}

机构：

[1] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA USA

[3] Boston Childrens Hosp, Dept Med, Boston, MA USA

[4] C Mondino Natl Neurol Inst, Child Neurol & Psychiat Unit, Pavia, Italy

[5] Univ Pavia, Dept Brain & Behav Sci, Unit Child Neurol & Psychiat, I-27100 Pavia, Italy

[6] Hop Necker Enfants Malad, AP HP, Imagine Fdn, Dept Pediat Immunol & Rheumatol,INSERM U76, Paris, France

[7] Alder Hey Childrens Natl Hlth Serv NHS Fdn Trus, Dept Paediat Rheumatol, Liverpool, Merseyside, England

[8] IRCCS Stella Mans, Dept Dev Neurosci, Pisa, Italy

[9] Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England

[10] CHU Dijon, Serv Pediat 1, Dijon, France

[11] AOU Meyer, Dept Pediat, Florence, Italy

[12] Univ Florence, Florence, Italy

[13] Univ Colorado, Sch Med, Dept Pediat, Div Pediat Neurol, Denver, CO USA

[14] Rainbow House NHS Ayrshire & Arran, Dept Paediat, Irvine, CA USA

[15] Univ Sydney, Childrens Hosp Westmead, Neuroimmunol Grp, Sydney, NSW 2006, Australia

[16] Royal Hosp Sick Children, Dept Paediat Rheumatol, Glasgow G3 8SJ, Lanark, Scotland

[17] Katholieke Univ Leuven Hosp, Dept Paediat Neurol, Louvain, Belgium

[18] Hop Necker Enfants Malad, AP HP, INSERM U768, Dept Pediat Neurol, Paris, France

[19] CHU Dijon, Hop Enfants, Ctr Genet, Dijon, France

[20] Univ Bourgogne, Dijon, France

[21] Univ Brescia, Dept Clin & Expt Sci, Civil Hosp, Child Neurol & Psychiat Unit, Brescia, Italy

[22] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France

[23] INSERM, UMRS 957, Nantes, France

[24] McMaster Univ, Dept Pediat, Div Gen Pediat, McMaster Childrens Hosp, Hamilton, ON, Canada

[25] Univ & Fac Med Paris Descartes, Paris, France

[26] McMaster Univ, McMaster Childrens Hosp, Clin Genet Program, Dept Pediat, Hamilton, ON, Canada

[27] Leeds Teaching Hosp NHS Trust, Dept Paediat Neurol, Leeds, W Yorkshire, England

[28] Univ Sao Paulo, Clin Hosp Ribeirao Preto, Sao Paulo, Brazil

[29] Giannina Gaslim Inst, Dept Neurosci, Operat Unit Child Neuropsychiat, Genoa, Italy

[30] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland

[31] Univ Sydney, Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2006, Australia

[32] Grp Hosp Pitie Salpetriere, AP HP, Dept Genet, Paris, France

[33] Giannina Gaslini Inst, Genoa, Italy

[34] Univ Milan, San Paolo Hosp, Clin Dept Pediat, Milan, Italy

[35] Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England

[36] HUEP, AP HP, Hop A Trousseau, Serv Neuropediat,Ctr Reference Neurogenet, Paris, France

[37] Univ Paris 06, Paris, France

[38] INSERM U676, Paris, France

[39] Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat Rheumatol, ZA-79250 Cape Town, South Africa

[40] So Gen Hosp, Dept Clin Genet, Glasgow G51 4TF, Lanark, Scotland

[41] Childrens Natl Med Ctr, Dept Pediat Neurol, Washington, DC 20010 USA

[42] CHU Rouen, Hop Charles Nicolle, Serv Neonatal & Reanimat, Rouen, France

[43] Hosp Dona Estefania, Ctr Hosp Lisboa Cent, Dept Neurol, Lisbon, Portugal

[44] McMaster Univ, McMaster Childrens Hosp, Dept Pediat, Div Pediat Neurol, Hamilton, ON, Canada

[45] US Natl Inst Hlth Undiagnosed Dis Program, Bethesda, MD USA

[46] Royal Hosp Sick Children, Fraser Allander Neurosci Unit, Paediat Neurosci Res Grp, Glasgow G3 8SJ, Lanark, Scotland

[47] Univ Glasgow, Coll Med Vet & Life Sci, Sch Med, Glasgow, Lanark, Scotland

来源：

NATURE GENETICS | 2014年 / 46卷 / 05期

基金：

欧洲研究理事会;

关键词：

AICARDI-GOUTIERES-SYNDROME; DYSCHROMATOSIS SYMMETRICA HEREDITARIA; EXPRESSION SIGNATURE; DSRNA RECOGNITION; MDA5; FILAMENTS; AUTOIMMUNITY; LUPUS; TREX1; MICE; DISORDERS;

D O I：

10.1038/ng.2933

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutieres syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

引用

页码：503 / 509

页数：7

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