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

Oleh:

Rice, Gillian I ; Duany, Yoandris del Toro ; Jenkinson, Emma M ; Forte, Gabriella M A ; Ariaudo, Giada

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Nature Genetics vol. 46 no. 05 (May 2014), page 503 - 509.

Ketersediaan

Perpustakaan FK Nomor Panggil: N12.K Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

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.

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