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

Authors

  • Gillian I. Rice,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • Martin A.M. Reijns,

    1. Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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  • Stephanie R. Coffin,

    1. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina
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  • Gabriella M.A. Forte,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • Beverley H. Anderson,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • Marcin Szynkiewicz,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • Hannah Gornall,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • David Gent,

    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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  • Andrea Leitch,

    1. Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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  • Maria P. Botella,

    1. Unidad de Neuropediatría, Servicio de Pediatría, Hospital Universitario Araba, Vitoria-Gasteiz, Spain
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  • Elisa Fazzi,

    1. Department of Clinical and Experimental Sciences, Medical School, University of Brescia, Unit of Child Neurology and Psychiatry, Civil Hospital, Brescia, Italy
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  • Blanca Gener,

    1. Department of Genetics, BioCruces Health Research Institute, Cruces University Hospital, Bizkaia, Spain
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  • Lieven Lagae,

    1. Paediatric Neurology – Epilepsy, UZ Leuven, Campus Gasthuisberg, Leuven, Belgium
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  • Ivana Olivieri,

    1. Unit of Child Neurology and Psychiatry, IRCCS “C. Mondino National Institute of Neurology” Foundation, Pavia, Italy
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  • Simona Orcesi,

    1. Unit of Child Neurology and Psychiatry, IRCCS “C. Mondino National Institute of Neurology” Foundation, Pavia, Italy
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  • Kathryn J. Swoboda,

    1. Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah
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  • Fred W. Perrino,

    1. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina
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  • Andrew P. Jackson,

    1. Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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  • Yanick J. Crow

    Corresponding author
    1. Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom
    2. St. Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
    • Correspondence to: Yanick J. Crow, Genetic Medicine, 6th Floor, St Mary's Hospital, Oxford Road, Manchester M13 9WL, United Kingdom. E-mail: yanickcrow@mac.com

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  • Contract grant sponsors: European Union's Seventh Framework Programme (FP7/2007–2013) (241779); MRC Senior Clinical Fellowship; the Lister Institute for Preventative Medicine; National Institutes of Health Grant GM069962; the Alliance for Lupus Research 179222; National Institutes of Health Postdoctoral Fellowship Award F32GM095290.

  • Communicated by Mario Tosi

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.

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