Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in aicardi-Goutières syndrome

Gillian I. Rice, Martin A M Reijns, Stephanie R. Coffin, Gabriella M A Forte, Beverley H. Anderson, Marcin Szynkiewicz, Hannah Gornall, David Gent, Andrea Leitch, Maria P. Botella, Elisa Fazzi, Blanca Gener, Lieven Lagae, Ivana Olivieri, Simona Orcesi, Kathryn J. Swoboda, Fred W. Perrino, Andrew P. Jackson, Yanick J. Crow

Research output: Contribution to journalArticlepeer-review

Abstract

Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.

Original languageEnglish
Pages (from-to)1066-1070
Number of pages5
JournalHuman Mutation
Volume34
Issue number8
DOIs
Publication statusPublished - Aug 2013

Keywords

  • AGS
  • Aicardi-Goutières syndrome
  • RNASEH2A
  • Splicing
  • Synonymous mutations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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