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

Gillian I Rice; Yoandris Del Toro Duany; Emma M Jenkinson; Gabriella M A Forte; Beverley H Anderson; Giada Ariaudo; Brigitte Bader-Meunier; Eileen M Baildam; Roberta Battini; Michael W Beresford; Manuela Casarano; Mondher Chouchane; Rolando Cimaz; Abigail E Collins; Nuno J V Cordeiro; Russell C Dale; Joyce E Davidson; Liesbeth De Waele; Isabelle Desguerre; Laurence Faivre; Elisa Fazzi; Bertrand Isidor; Lieven Lagae; Andrew R Latchman; Pierre Lebon; Chumei Li; John H Livingston; Charles M Lourenço; Maria Margherita Mancardi; Alice Masurel-Paulet; Iain B Mcinnes; Manoj P Menezes; Cyril Mignot; James O'Sullivan; Simona Orcesi; Paolo P Picco; Enrica Riva; Robert A Robinson; Diana Rodriguez; Elisabetta Salvatici; Christiaan Scott; Marta Szybowska; John L Tolmie; Adeline Vanderver; Catherine Vanhulle; Jose Pedro Vieira; Kate Webb; Robyn N Whitney; Simon G Williams; Lynne A Wolfe; Sameer M Zuberi; Sun Hur; Yanick J Crow

doi:10.1038/ng.2933

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

Gillian I Rice, Yoandris Del Toro Duany, Emma M Jenkinson, Gabriella M A Forte, Beverley H Anderson, Giada Ariaudo, Brigitte Bader-Meunier, Eileen M Baildam, Roberta Battini, Michael W Beresford, Manuela Casarano, Mondher Chouchane, Rolando Cimaz, Abigail E Collins, Nuno J V Cordeiro, Russell C Dale, Joyce E Davidson, Liesbeth De Waele, Isabelle Desguerre, Laurence FaivreElisa Fazzi, Bertrand Isidor, Lieven Lagae, Andrew R Latchman, Pierre Lebon, Chumei Li, John H Livingston, Charles M Lourenço, Maria Margherita Mancardi, Alice Masurel-Paulet, Iain B Mcinnes, Manoj P Menezes, Cyril Mignot, James O'Sullivan, Simona Orcesi, Paolo P Picco, Enrica Riva, Robert A Robinson, Diana Rodriguez, Elisabetta Salvatici, Christiaan Scott, Marta Szybowska, John L Tolmie, Adeline Vanderver, Catherine Vanhulle, Jose Pedro Vieira, Kate Webb, Robyn N Whitney, Simon G Williams, Lynne A Wolfe, Sameer M Zuberi, Sun Hur, Yanick J Crow

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Abstract / Description of output

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-Goutières 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.

Original language	English
Pages (from-to)	503-509
Journal	Nature Genetics
Volume	46
Issue number	5
Early online date	30 Mar 2014
DOIs	https://doi.org/10.1038/ng.2933
Publication status	Published - 1 May 2014

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Yanick Crow
- Deanery of Molecular, Genetic and Population Health Sciences - Chair of Genomic Medicine
- Centre for Genomic and Experimental Medicine
- Edinburgh Neuroscience
Person: Academic: Research Active

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Rice, G. I., Del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., Bader-Meunier, B., Baildam, E. M., Battini, R., Beresford, M. W., Casarano, M., Chouchane, M., Cimaz, R., Collins, A. E., Cordeiro, N. J. V., Dale, R. C., Davidson, J. E., De Waele, L., Desguerre, I., ... Crow, Y. J. (2014). Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nature Genetics, 46(5), 503-509. Advance online publication. https://doi.org/10.1038/ng.2933

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

abstract = "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-Gouti{\`e}res 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.",

author = "Rice, {Gillian I} and {Del Toro Duany}, Yoandris and Jenkinson, {Emma M} and Forte, {Gabriella M A} and Anderson, {Beverley H} and Giada Ariaudo and Brigitte Bader-Meunier and Baildam, {Eileen M} and Roberta Battini and Beresford, {Michael W} and Manuela Casarano and Mondher Chouchane and Rolando Cimaz and Collins, {Abigail E} and Cordeiro, {Nuno J V} and Dale, {Russell C} and Davidson, {Joyce E} and {De Waele}, Liesbeth and Isabelle Desguerre and Laurence Faivre and Elisa Fazzi and Bertrand Isidor and Lieven Lagae and Latchman, {Andrew R} and Pierre Lebon and Chumei Li and Livingston, {John H} and Louren{\c c}o, {Charles M} and Mancardi, {Maria Margherita} and Alice Masurel-Paulet and Mcinnes, {Iain B} and Menezes, {Manoj P} and Cyril Mignot and James O'Sullivan and Simona Orcesi and Picco, {Paolo P} and Enrica Riva and Robinson, {Robert A} and Diana Rodriguez and Elisabetta Salvatici and Christiaan Scott and Marta Szybowska and Tolmie, {John L} and Adeline Vanderver and Catherine Vanhulle and Vieira, {Jose Pedro} and Kate Webb and Whitney, {Robyn N} and Williams, {Simon G} and Wolfe, {Lynne A} and Zuberi, {Sameer M} and Sun Hur and Crow, {Yanick J}",

year = "2014",

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doi = "10.1038/ng.2933",

language = "English",

volume = "46",

pages = "503--509",

journal = "Nature Genetics",

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Rice, GI, Del Toro Duany, Y, Jenkinson, EM, Forte, GMA, Anderson, BH, Ariaudo, G, Bader-Meunier, B, Baildam, EM, Battini, R, Beresford, MW, Casarano, M, Chouchane, M, Cimaz, R, Collins, AE, Cordeiro, NJV, Dale, RC, Davidson, JE, De Waele, L, Desguerre, I, Faivre, L, Fazzi, E, Isidor, B, Lagae, L, Latchman, AR, Lebon, P, Li, C, Livingston, JH, Lourenço, CM, Mancardi, MM, Masurel-Paulet, A, Mcinnes, IB, Menezes, MP, Mignot, C, O'Sullivan, J, Orcesi, S, Picco, PP, Riva, E, Robinson, RA, Rodriguez, D, Salvatici, E, Scott, C, Szybowska, M, Tolmie, JL, Vanderver, A, Vanhulle, C, Vieira, JP, Webb, K, Whitney, RN, Williams, SG, Wolfe, LA, Zuberi, SM, Hur, S & Crow, YJ 2014, 'Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling', Nature Genetics, vol. 46, no. 5, pp. 503-509. https://doi.org/10.1038/ng.2933

TY - JOUR

T1 - Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling

AU - Rice, Gillian I

AU - Del Toro Duany, Yoandris

AU - Jenkinson, Emma M

AU - Forte, Gabriella M A

AU - Anderson, Beverley H

AU - Ariaudo, Giada

AU - Bader-Meunier, Brigitte

AU - Baildam, Eileen M

AU - Battini, Roberta

AU - Beresford, Michael W

AU - Casarano, Manuela

AU - Chouchane, Mondher

AU - Cimaz, Rolando

AU - Collins, Abigail E

AU - Cordeiro, Nuno J V

AU - Dale, Russell C

AU - Davidson, Joyce E

AU - De Waele, Liesbeth

AU - Desguerre, Isabelle

AU - Faivre, Laurence

AU - Fazzi, Elisa

AU - Isidor, Bertrand

AU - Lagae, Lieven

AU - Latchman, Andrew R

AU - Lebon, Pierre

AU - Li, Chumei

AU - Livingston, John H

AU - Lourenço, Charles M

AU - Mancardi, Maria Margherita

AU - Masurel-Paulet, Alice

AU - Mcinnes, Iain B

AU - Menezes, Manoj P

AU - Mignot, Cyril

AU - O'Sullivan, James

AU - Orcesi, Simona

AU - Picco, Paolo P

AU - Riva, Enrica

AU - Robinson, Robert A

AU - Rodriguez, Diana

AU - Salvatici, Elisabetta

AU - Scott, Christiaan

AU - Szybowska, Marta

AU - Tolmie, John L

AU - Vanderver, Adeline

AU - Vanhulle, Catherine

AU - Vieira, Jose Pedro

AU - Webb, Kate

AU - Whitney, Robyn N

AU - Williams, Simon G

AU - Wolfe, Lynne A

AU - Zuberi, Sameer M

AU - Hur, Sun

AU - Crow, Yanick J

PY - 2014/5/1

Y1 - 2014/5/1

N2 - 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-Goutières 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.

AB - 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-Goutières 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.

U2 - 10.1038/ng.2933

DO - 10.1038/ng.2933

M3 - Article

SN - 1061-4036

VL - 46

SP - 503

EP - 509

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

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