title: Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.
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.
authors.affiliation: Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.forename: Martin A M
authors.initials: MA
authors.lastname: Reijns
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Coffin
authors.forename: Gabriella M A
authors.initials: GM
authors.lastname: Forte
authors.forename: Beverley H
authors.initials: BH
authors.lastname: Anderson
authors.forename: Marcin
authors.initials: M
authors.lastname: Szynkiewicz
authors.forename: Hannah
authors.initials: H
authors.lastname: Gornall
authors.forename: David
authors.initials: D
authors.lastname: Gent
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.forename: Maria P
authors.initials: MP
authors.lastname: Botella
authors.forename: Elisa
authors.initials: E
authors.lastname: Fazzi
authors.forename: Blanca
authors.initials: B
authors.lastname: Gener
authors.forename: Lieven
authors.initials: L
authors.lastname: Lagae
authors.forename: Ivana
authors.initials: I
authors.lastname: Olivieri
authors.forename: Simona
authors.initials: S
authors.lastname: Orcesi
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D017354:Point Mutation; D022821:RNA Splice Sites; D016914:Ribonuclease H / Q000235:genetics* / Q000378:metabolism
chemical_list: D022821:RNA Splice Sites; C091139:ribonuclease HII; D016914:Ribonuclease H
keywords: AGS; Aicardi-Goutières syndrome; RNASEH2A; splicing; synonymous mutations