Details

Autor(en) / Beteiligte

• 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.

Titel

Synonymous Mutations in RNASEH2A Create Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi-Goutières Syndrome

Ist Teil von

• Human mutation, 2013-08, Vol.34 (8), p.1066-1070

Ort / Verlag

United States: Blackwell Publishing Ltd

Erscheinungsjahr

2013

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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. Aicardi‐Goutières syndrome (AGS) is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1 or ADAR1. In this study, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A, resulting in a loss of RNase H2 enzyme activity and the consequent AGS phenotype. In our cohort of 265 AGS pedigrees, four of thirteen families with RNASEH2A mutations harbor one of the two splicing variants described here.