The Aicardi-Goutières syndrome. Molecular and clinical features of RNAse deficiency and microRNA overload.

Intracellular RNAses are involved in various functions, including microRNA maturation and turnover.
Mutations occurring in genes encoding RNAses cause Aicardi–Goutiéres syndrome (AGS). AGS mutations
silence RNAse activity, thus inducing accumulation of endogenous RNAs, mainly consisting of short
RNAs and microRNAs. Overload of intracellular RNA triggers Toll like receptor-dependent interferonalpha
production in the brain, which in turn activates neurotoxic lymphocytes and inhibits angiogenesis
thus inducing the typical clinical phenotype of AGS. However, these pathogenic mechanisms are attenuated
after three years of age by the endogenous production of DNAJP58IPK and Cystatin F, which arrest
AGS progression. Because RNAses are involved in microRNA turnover, we evaluated the expression of 957
microRNAs in lymphocytes from AGS patients and control patients. Our results indicate that microRNA
overload occurs in AGS patients. This upregulation inhibits microRNA turnover impeding the synthesis
of the novel microRNAs required for the differentiation and myelination of the brain during the initial
period of postnatal life. These pathogenic mechanisms result in AGS, a neurological syndrome characterized
by irritability, mild hyperpyrexia, pyramidal and extrapyramidal signs, and spastic-dystonic
tetraplegia. Typical cerebrospinal fluid alterations include lymphocytosis and elevated interferon-alpha
levels. Brain imaging demonstrates cerebral calcifications, white matter abnormalities, and progressive
cerebral atrophy.Thus, evidence exists that mutations silencing intracellular RNases affect microRNA
turnover resulting in the severe clinical consequences in the brain characterizing the clinical feature of
AGS.