Genetics

Genetics

Aicardi-Goutières syndrome is an encephalopathy with a genetic aetiology. It has a primarily autosomal recessive (AR) pattern of inheritance.
The disease is caused by mutation of one of the 7 disease-causing genes so far discovered, all of which play a role in the production of enzymes involved in the clearance of nucleic acids (DNA and RNA). 
In more detail, the first gene identified is located on chromosome 3 (TREX1/AGS1) and it encodes a protein (exonuclease 3'-5' DNA) responsible for removing fragments of non-coding DNA, deposited in the cytoplasm of cells. DNA consists of coding DNA (about 1% of the total), which contains the genes for the production of proteins, and non-coding DNA (most of the remaining DNA), whose function is not yet known, and which is made up, in part, of what are thought to be residues of primordial viruses which, in the course of evolution, have become integrated into our chromosomes. 
These primordial viruses, mimicking a process that occurs during viral infections (caused by exogenous viruses), can break away from the DNA and alter the cell replication process. Normally, cells contain defence mechanisms, such as the TREX1 protein, that block the activity of these elements, eliminating their DNA.
Loss of function of exonucleases results in an increase in cytoplasmic DNA, as occurs in the case of TREX1 mutations.
The identification of the first gene was followed by descriptions of the next three disease-causing genes, which encode three subunits of a single enzyme complex: ribonuclease H2, and are located, respectively, on chromosomes 13 (AGS2/RNASEH2B), 11 (AGS3/RNASEH2C) and 19 (AGS4/ RNASEH2A). 
This ribonuclease removes both "hybrids" (small sequences of paired DNA and RNA) and single ribonucleotides erroneously incorporated into DNA during the replication process. The duplication of DNA molecules is necessary for cell proliferation, and replication is the process that allows this. It is possible that, during this process, single ribonucleotides, i.e. the “building blocks” of nucleic acid (named RNA), are incorrectly incorporated into DNA, leading to the formation of unstable DNA. Indeed, the lack of ribonuclease H2 results in the formation of unstable DNA and alters the normal cellular repair mechanisms. 
In 2009, the fifth gene (SAMHD1/AGS5) was identified. SAMHD1 is located on chromosome 20 and encodes an enzyme with a regulatory role in nucleic acid metabolism. This enzyme, through a highly complex mechanism of action, blocks DNA replication in the presence of a viral infection. In individuals with AGS, therefore, mutation of the SAMHD1 gene, resulting in absence of the enzyme it encodes, leads to a build-up of nucleic acids in the cell.  
In 90% of patients with AGS, one of these 5 genes is mutated. 
In 2012, the sixth gene (ADAR1/AGS6) was identified. It is located on chromosome 1 and encodes an enzyme (called RNA-specific adenosine deaminase) whose mechanism of action is not yet fully understood. It is hypothesised that ADAR1 prevents the build-up of RNA in the cytoplasm and that it may regulate the expression of interferon-stimulated genes. 
Recently a further gene has been identified whose mutation may result in AGS. In this case the gene, IFIH1/AGS7, encodes a protein (MDA5) that acts as a cytoplasmic "sensor" (also called "receptor") of the presence of double-stranded RNA, which is usually of viral origin. In this case too, therefore, the gene is involved in the metabolism of nucleic acids and in the response to infectious agents: if the gene is mutated, the protein produced, that is to say the sensor, binds more “avidly” to the cytoplasmic RNA and causes an excessive activation of the interferon response.
As regards the frequency of mutations in the different genes, mutations in RNASEH2B, found in 35-40% of AGS patients (usually of Italian and European origin), are the most frequent, followed by mutations in TREX1 (23-25%), which is the gene frequently mutated in northern European families. RNASEH2C mutations are rarer (12-15%) and almost always found in the Pakistani population; 10-13% of patients have mutations in SAMHD1 while mutations in RNASEH2A have been described in only 5% of cases. At present, the most recently identified genes, ADAR1 and IFIH1, have lower mutation rates, being found to be responsible for the disease in around 8% and 3.8% of cases respectively.
As already indicated, in almost all cases the disease is inherited as an autosomal recessive trait (which means that the parents of a child with AGS are carriers of the disease and have a 25% risk of having another affected child with every new pregnancy); the exceptions are cases carrying   mutations (heterozygous and dominant) in the most recently identified gene, IFIH1; there also exist descriptions of cases of AGS inherited as a dominant trait caused by de novo heterozygous mutations of TREX1 and ADAR1. 
The important progress made, in recent years, in understanding the genetic basis of the syndrome has made it possible, on the one hand, to characterise in more detail its broad phenotypic spectrum and to look for a clearer genotype-phenotype correlation, and on the other to better define the AGS disease model in order to support the search for new treatments.
The first genotype-phenotype correlations established concerned the (numerically largest) group of individuals with mutations in the first four genes identified; in particular, the very early-onset forms with a more severe clinical picture and worse outcome, as well as a reduced chance of surviving beyond the first years of life, have been described mainly in association with mutations in TREX1, RNASEH2A and RNASEH2C, whereas the forms characterised by onset after the first months of life, which also lead to a severe clinical picture but are associated with a better life expectancy, are more frequent in patients with mutations in RNASEH2B, as are the atypical presentations in which there is preservation of motor and intellectual abilities.
It has been found that when SAMHD1 is the mutated gene, patients can initially have a less severe neurological picture, however, as we have seen, these patients are at risk of sometimes serious cerebrovascular complications; some develop arthropathy with progressive contractures. 
    Bilateral striatal necrosis resulting in the presence of severe dystonic-rigid clinical features is, instead, the distinctive phenotype in patients with mutations in ADAR1, in whom the onset can occur even after the first year of life.
The phenotypic spectrum associated with mutations in the AGS genes is still expanding, as shown by recent reports of classic cases of uncomplicated spastic paraplegia (clinical signs involving only the lower limbs, normal intelligence, normal brain MRI, and positive interferon signature present only in some cases) due to mutations in AGS genes (in particular RNASEH2B/AGS2, ADAR1/AGS6, IFIH1/AGS7). The fact that these genetic mutations can give rise to different clinical pictures, not necessarily classifiable as AGS, strengthens the suggestion that there exist factors, as yet unknown and probably of a genetic nature, that are capable of modifying the effect of mutations in the AGS genes. 
Recently, it has been suggested that mutations in another known gene, RNASET2, causing cystic leukoencephalopathy without megalencephaly, can provoke clinical and neuroradiological pictures overlapping with AGS. It is likely that in the near future the relations between these clinical entities will be better clarified.