Title: Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome
Authors: Rice, Gillian I ×
Reijns, Martin A M
Coffin, Stephanie R
Forte, Gabriella M A
Anderson, Beverley H
Szynkiewicz, Marcin
Gornall, Hannah
Gent, David
Leitch, Andrea
Botella, Maria P
Fazzi, Elisa
Gener, Blanca
Lagae, Lieven
Olivieri, Ivana
Orcesi, Simona
Swoboda, Kathryn J
Perrino, Fred W
Jackson, Andrew P
Crow, Yanick J #
Issue Date: Aug-2013
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:34 issue:8 pages:1066-70
Article number: 10.1002/humu.22336
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.
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Brain & Metabolism Section (-)
× corresponding author
# (joint) last author

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