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Searching for the Aicardi–Goutières syndrome genes: TREX1 and ribonuclease H2 make the cut

Aicardi-Goutières syndrome (AGS) is a rare autosomal recessive disorder first described in 1984, with a wide range of symptoms including encephalopathy, basal ganglia calcification, motor deficits, spasticity, dystonia, skin lesions and cerebrospinal fluid lymphocytosis. AGS symptoms usually appear during the first 6 months of life, and the disease is severe and progressive, with 25% of patients dying before the age of 17. AGS shares many symptoms with other diseases including Cree encephalopathy, which found in the native Canadian Cree tribe, microcephaly, intracranial calcification syndrome and systemic lupus erythematosus. AGS has been difficult to diagnose because the symptoms overlap with those of other diseases, most notably those associated with in utero viral infections (1). Because the specific genetic defects involved in the pathogenesis of AGS had been elusive, prenatal testing for AGS has not been possible. This, however, may change with the recent discoveries made by Crow and colleagues reported in two papers in the August 2006 issue of Nature Genetics. The group of researchers reports the mutations in four genes as the underlying cause of AGS. One is the TREX1 gene encoding a major mammalian 3#–5# DNA exonuclease (otherwise known as DNase III) responsible for degrading nicked DNA strands. The other mutations are in three genes encoding different subunits of ribonuclease (RNase) H2, an RNase responsible for cleaving ribonucleotides from RNA:DNA complexes and DNA:DNA duplexes. The authors directed their attention to the TREX1 gene as a possible culprit in AGS based on previous observation that TREX1-deficient mice show spontaneous inflammatory myocarditis under pathogen-free conditions (2) and the fact that the TREX1 gene lies in the AGS1 critical region on chromosome 3p21, previously identified by the authors. Screening of theTREX1 gene in 10 families from various ethnic backgrounds with members diagnosed with AGS led to the identification of five distinct TREX1 mutations (Fig. 1). These include missense mutations leading to single amino acid substitutions in the three prime repair exonuclease (TREX1) protein, a three-nucleotide insertion leading to the duplication of an aspartate residue in one of the TREX1 catalytic domains and protein truncation mutations. These mutations segregated with the disease in all affected families. Using lymphoblastoid and fibroblast cell lines derived from affected individuals, the authors confirmed the loss of TREX1 enzyme activity as a result of three of the five discovered mutations, suggesting that the loss of function of the 3#exonuclease activity of TREX1 leads to the symptoms of AGS. In the search of other AGS loci, the authors also identified two additional loci AGS2 on chromosome 13q14.3 and AGS3 on chromosome 11q13.2 in the affected individuals by creating a high-density map of microsatellite markers. So what are the other genes beside TREX1 that are involved in AGS? In fact, the authors found that genes encoding different subunits of the same protein RNase H2 are found in the critical loci. Missense and non-sense mutations in the H2B subunit gene that lies in the AGS2 critical region were identified in 18 affected families. Two missense mutations were found in the H2C subunit in the AGS3 critical region in six families. The authors were then left with the question of whether mutations in the gene for the third