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

Research output: Contribution to journalArticle

253 Citations (Scopus)

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-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 languageEnglish
Pages (from-to)503-509
Number of pages7
JournalNature Genetics
Volume46
Issue number5
DOIs
Publication statusPublished - 2014

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Interferon Type I
Interferons
Aicardi Syndrome
Phenotype
Mutation
Double-Stranded RNA
Nucleic Acids
Antiviral Agents
Immunity
Up-Regulation
RNA
Ligands
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Rice, G. I., Del Toro Duany, Y., Jenkinson, E. M., Forte, G. M. A., Anderson, B. H., Ariaudo, G., ... 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. https://doi.org/10.1038/ng.2933

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type i interferon signaling. / Rice, Gillian I.; Del Toro Duany, Yoandris; Jenkinson, Emma M.; Forte, Gabriella M A; Anderson, Beverley H.; Ariaudo, Giada; Bader-Meunier, Brigitte; Baildam, Eileen M.; Battini, Roberta; Beresford, Michael W.; Casarano, Manuela; Chouchane, Mondher; Cimaz, Rolando; Collins, Abigail E.; Cordeiro, Nuno J V; Dale, Russell C.; Davidson, Joyce E.; De Waele, Liesbeth; Desguerre, Isabelle; Faivre, Laurence; Fazzi, Elisa; Isidor, Bertrand; Lagae, Lieven; Latchman, Andrew R.; Lebon, Pierre; Li, Chumei; Livingston, John H.; Lourenço, Charles M.; Mancardi, Maria Margherita; Masurel-Paulet, Alice; McInnes, Iain B.; Menezes, Manoj P.; Mignot, Cyril; O'Sullivan, James; Orcesi, Simona; Picco, Paolo P.; Riva, Enrica; Robinson, Robert A.; Rodriguez, Diana; Salvatici, Elisabetta; Scott, Christiaan; Szybowska, Marta; Tolmie, John L.; Vanderver, Adeline; Vanhulle, Catherine; Vieira, Jose Pedro; Webb, Kate; Whitney, Robyn N.; Williams, Simon G.; Wolfe, Lynne A.; Zuberi, Sameer M.; Hur, Sun; Crow, Yanick J.

In: Nature Genetics, Vol. 46, No. 5, 2014, p. 503-509.

Research output: Contribution to journalArticle

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
Rice, Gillian I. ; Del Toro Duany, Yoandris ; Jenkinson, Emma M. ; Forte, Gabriella M A ; Anderson, Beverley H. ; Ariaudo, Giada ; Bader-Meunier, Brigitte ; Baildam, Eileen M. ; Battini, Roberta ; Beresford, Michael W. ; Casarano, Manuela ; Chouchane, Mondher ; Cimaz, Rolando ; Collins, Abigail E. ; Cordeiro, Nuno J V ; Dale, Russell C. ; Davidson, Joyce E. ; De Waele, Liesbeth ; Desguerre, Isabelle ; Faivre, Laurence ; Fazzi, Elisa ; Isidor, Bertrand ; Lagae, Lieven ; Latchman, Andrew R. ; Lebon, Pierre ; Li, Chumei ; Livingston, John H. ; Lourenço, Charles M. ; Mancardi, Maria Margherita ; Masurel-Paulet, Alice ; McInnes, Iain B. ; Menezes, Manoj P. ; Mignot, Cyril ; O'Sullivan, James ; Orcesi, Simona ; Picco, Paolo P. ; Riva, Enrica ; Robinson, Robert A. ; Rodriguez, Diana ; Salvatici, Elisabetta ; Scott, Christiaan ; Szybowska, Marta ; Tolmie, John L. ; Vanderver, Adeline ; Vanhulle, Catherine ; Vieira, Jose Pedro ; Webb, Kate ; Whitney, Robyn N. ; Williams, Simon G. ; Wolfe, Lynne A. ; Zuberi, Sameer M. ; Hur, Sun ; Crow, Yanick J. / Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type i interferon signaling. In: Nature Genetics. 2014 ; Vol. 46, No. 5. pp. 503-509.
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AU - De Waele, Liesbeth

AU - Desguerre, Isabelle

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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.

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AU - O'Sullivan, James

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