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

Rice, G. I. et al. (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), pp. 503-509. (doi:10.1038/ng.2933) (PMID:24686847) (PMCID:PMC4004585)

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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.

Item Type:Articles (Letter)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Zuberi, Dr Sameer and Tolmie, Dr John
Authors: 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., Faivre, L., Fazzi, E., Isidor, B., Lagae, L., Latchman, A. R., Lebon, P., Li, C., Livingston, J. H., Lourenço, C. M., Mancardi, M. M., Masurel-Paulet, A., McInnes, I. B., Menezes, M. P., Mignot, C., O'Sullivan, J., Orcesi, S., Picco, P. P., Riva, E., Robinson, R. A., Rodriguez, D., Salvatici, E., Scott, C., Szybowska, M., Tolmie, J. L., Vanderver, A., Vanhulle, C., Vieira, J. P., Webb, K., Whitney, R. N., Williams, S. G., Wolfe, L. A., Zuberi, S. M., Hur, S., and Crow, Y. J.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN:1061-4036
ISSN (Online):1546-1718

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