Mutations in the genes encoding the RNaseH2 and TREX1 nucleases have been 
identified in patients with Aicardi-Goutieres syndrome (AGS). To determine if 
the AGS RNaseH2 mutations result in the loss of nuclease activity, the human 
wild-type RNaseH2 and four mutant complexes that constitute the majority of 
mutations identified in AGS patients have been prepared and tested for 
ribonuclease H activity. The heterotrimeric structures of the mutant RNaseH2 
complexes are intact. Furthermore, the ribonuclease H activities of the mutant 
complexes are indistinguishable from the wild-type enzyme with the exception of 
the RNaseH2 subunit A (Gly37Ser) mutant, which exhibits some evidence of altered 
nuclease specificity. These data indicate that the mechanism of RNaseH2 
dysfunction in AGS cannot be simply explained by loss of ribonuclease H activity 
and points to a more complex mechanism perhaps mediated through altered 
interactions with as yet identified nucleic acids or protein partners.