Mutant alleles in Aicardi-Goutieres syndrome patients produce a disfunctional RNASET2 protein associated with alterations in interferon signalling.

Aicardi-Goutières Syndrome (AGS), a genetically determined, early onset Mendelian encephalopathy displaying phenotypic overlap with systemic lupus erythematosus and viral congenital infections, has been linked to mutations in several human genes involved in nucleic acid sensing, signaling or processing. A typical feature of AGS includes an “interferon signature”, represented by increased levels of both interferon-alpha (IFN-) and IFN-- regulated genes in cerebrospinal fluid and peripheral blood, which collectively define AGS as an inflammatory disease triggered by induction of an excessive type-I interferon-mediated innate immune response, possibly driven by the accumulation of endogenous nucleic acids. The RNASET2 gene encodes the only human member of the highly conserved T2/Rh/S family of extracellular ribonucleases and has been consistently reported to be involved in innate immune response regulation. Here, we show that several mutant RNASET2 alleles carried by AGS patients encode a functionally defective protein, whose catalytic activity, intracellular distribution, and secretion pattern are significantly impaired, compared to the wild-type allele-encoded protein. Furthermore, expression of the mutant alleles in the RNASET2-null MCF7 cancer cell line was found to be associated with the AGS-associated interferon signature. We thus propose human RNASET2 as novel member of the increasing family of nucleic acid sensing/signalling genes involved in the pathogenesis of AGS.