RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases

Fred W. Perrino, Scott Harvey, Nadine M. Shaban, Thomas Hollis

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31 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)25-30
Number of pages6
JournalJournal of Molecular Medicine
Issue number1
StatePublished - Jan 2009

Bibliographical note

Funding Information:
Acknowledgments This work was supported by grants National Institutes of Health GM069962 (FWP), Alliance for Lupus Research 67692 (FWP), and American Cancer Society RSG-04-187-01-GMC (TH).


  • Aicardi-Goutieres syndrome
  • Immune activation
  • Nuclease
  • RNaseH2


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