Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Gillian I Rice; Paul R. Kasher; Gabriella M. A. Forte; Niamh M. Mannion; Sam M. Greenwood; Marcin Szynkiewicz; Jonathan E Dickerson; Sanjeev S Bhaskar; Massimiliano Zampini; Tracy A Briggs; Emma M Jenkinson; Carlos A Bacino; Roberta Battini; Enrico Bertini; Paul A Brogan; Louise A Brueton; Marialuisa Carpanelli; Corinne De Laet; Pascale de Lonlay; Mireia del Toro; Isabelle Desguerre; Elisa Fazzi; Angels Garcia-Cazorla; Arvid Heiberg; Masakazu Kawaguchi; Ram Kumar; Jean-Pierre S-M Lin; Charles M Lourenco; Alison M Male; Wilson Marques; Cyril Mignot; Ivana Olivieri; Simona Orcesi; Prab Prabhakar; Magnhild Rasmussen; Robert A Robinson; Flore Rozenberg; Johanna L Schmidt; Katharina Steindl; Tiong Y Tan; William G van der Merwe; Adeline Vanderver; Grace Vassallo; Emma L Wakeling; Evangeline Wassmer; Elizabeth Whittaker; John H Livingston; Pierre Lebon; Tamio Suzuki; Paul J McLaughlin; Liam P Keegan; Mary A O'Connell; Simon C Lovell; Yanick J Crow

doi:10.1038/ng.2414

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Gillian I Rice, Paul R. Kasher, Gabriella M. A. Forte, Niamh M. Mannion, Sam M. Greenwood, Marcin Szynkiewicz, Jonathan E Dickerson, Sanjeev S Bhaskar, Massimiliano Zampini, Tracy A Briggs, Emma M Jenkinson, Carlos A Bacino, Roberta Battini, Enrico Bertini, Paul A Brogan, Louise A Brueton, Marialuisa Carpanelli, Corinne De Laet, Pascale de Lonlay, Mireia del ToroIsabelle Desguerre, Elisa Fazzi, Angels Garcia-Cazorla, Arvid Heiberg, Masakazu Kawaguchi, Ram Kumar, Jean-Pierre S-M Lin, Charles M Lourenco, Alison M Male, Wilson Marques, Cyril Mignot, Ivana Olivieri, Simona Orcesi, Prab Prabhakar, Magnhild Rasmussen, Robert A Robinson, Flore Rozenberg, Johanna L Schmidt, Katharina Steindl, Tiong Y Tan, William G van der Merwe, Adeline Vanderver, Grace Vassallo, Emma L Wakeling, Evangeline Wassmer, Elizabeth Whittaker, John H Livingston, Pierre Lebon, Tamio Suzuki, Paul J McLaughlin, Liam P Keegan, Mary A O'Connell, Simon C Lovell, Yanick J Crow

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Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Iaith wreiddiol	Saesneg
Tudalennau (o-i)	1243–1248
Nifer y tudalennau	6
Cyfnodolyn	Nature Genetics
Cyfrol	44
Rhif cyhoeddi	11
Dyddiad ar-lein cynnar	23 Medi 2012
Dynodwyr Gwrthrych Digidol (DOIs)	https://doi.org/10.1038/ng.2414
Statws	Cyhoeddwyd - Tach 2012

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10.1038/ng.2414

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http://hdl.handle.net/2160/12777

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Rice, G. I., Kasher, P. R., Forte, G. M. A., Mannion, N. M., Greenwood, S. M., Szynkiewicz, M., Dickerson, J. E., Bhaskar, S. S., Zampini, M., Briggs, T. A., Jenkinson, E. M., Bacino, C. A., Battini, R., Bertini, E., Brogan, P. A., Brueton, L. A., Carpanelli, M., De Laet, C., de Lonlay, P., ... Crow, Y. J. (2012). Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nature Genetics, 44(11), 1243–1248. https://doi.org/10.1038/ng.2414

@article{fd39b656084f4da0af534487d9deea9a,

title = "Mutations in ADAR1 cause Aicardi-Gouti{\`e}res syndrome associated with a type I interferon signature",

abstract = "Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Gouti{\`e}res syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.",

keywords = "Adenosine Deaminase, Alu Elements, Animals, Autoimmune Diseases of the Nervous System, Exome, Gene Expression, Humans, Interferon Type I, Mice, Mutation, Nervous System Malformations, Protein Conformation, RNA, Double-Stranded, Sequence Analysis, DNA, Signal Transduction, Structure-Activity Relationship",

author = "Rice, {Gillian I} and Kasher, {Paul R.} and Forte, {Gabriella M. A.} and Mannion, {Niamh M.} and Greenwood, {Sam M.} and Marcin Szynkiewicz and Dickerson, {Jonathan E} and Bhaskar, {Sanjeev S} and Massimiliano Zampini and Briggs, {Tracy A} and Jenkinson, {Emma M} and Bacino, {Carlos A} and Roberta Battini and Enrico Bertini and Brogan, {Paul A} and Brueton, {Louise A} and Marialuisa Carpanelli and {De Laet}, Corinne and {de Lonlay}, Pascale and {del Toro}, Mireia and Isabelle Desguerre and Elisa Fazzi and Angels Garcia-Cazorla and Arvid Heiberg and Masakazu Kawaguchi and Ram Kumar and Lin, {Jean-Pierre S-M} and Lourenco, {Charles M} and Male, {Alison M} and Wilson Marques and Cyril Mignot and Ivana Olivieri and Simona Orcesi and Prab Prabhakar and Magnhild Rasmussen and Robinson, {Robert A} and Flore Rozenberg and Schmidt, {Johanna L} and Katharina Steindl and Tan, {Tiong Y} and {van der Merwe}, {William G} and Adeline Vanderver and Grace Vassallo and Wakeling, {Emma L} and Evangeline Wassmer and Elizabeth Whittaker and Livingston, {John H} and Pierre Lebon and Tamio Suzuki and McLaughlin, {Paul J} and Keegan, {Liam P} and O'Connell, {Mary A} and Lovell, {Simon C} and Crow, {Yanick J}",

year = "2012",

month = nov,

doi = "10.1038/ng.2414",

language = "English",

volume = "44",

pages = "1243–1248",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "11",

}

Rice, GI, Kasher, PR, Forte, GMA, Mannion, NM, Greenwood, SM, Szynkiewicz, M, Dickerson, JE, Bhaskar, SS, Zampini, M, Briggs, TA, Jenkinson, EM, Bacino, CA, Battini, R, Bertini, E, Brogan, PA, Brueton, LA, Carpanelli, M, De Laet, C, de Lonlay, P, del Toro, M, Desguerre, I, Fazzi, E, Garcia-Cazorla, A, Heiberg, A, Kawaguchi, M, Kumar, R, Lin, J-PS-M, Lourenco, CM, Male, AM, Marques, W, Mignot, C, Olivieri, I, Orcesi, S, Prabhakar, P, Rasmussen, M, Robinson, RA, Rozenberg, F, Schmidt, JL, Steindl, K, Tan, TY, van der Merwe, WG, Vanderver, A, Vassallo, G, Wakeling, EL, Wassmer, E, Whittaker, E, Livingston, JH, Lebon, P, Suzuki, T, McLaughlin, PJ, Keegan, LP, O'Connell, MA, Lovell, SC & Crow, YJ 2012, 'Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature', Nature Genetics, cyfrol. 44, rhif 11, tt. 1243–1248. https://doi.org/10.1038/ng.2414

TY - JOUR

T1 - Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

AU - Rice, Gillian I

AU - Kasher, Paul R.

AU - Forte, Gabriella M. A.

AU - Mannion, Niamh M.

AU - Greenwood, Sam M.

AU - Szynkiewicz, Marcin

AU - Dickerson, Jonathan E

AU - Bhaskar, Sanjeev S

AU - Zampini, Massimiliano

AU - Briggs, Tracy A

AU - Jenkinson, Emma M

AU - Bacino, Carlos A

AU - Battini, Roberta

AU - Bertini, Enrico

AU - Brogan, Paul A

AU - Brueton, Louise A

AU - Carpanelli, Marialuisa

AU - De Laet, Corinne

AU - de Lonlay, Pascale

AU - del Toro, Mireia

AU - Desguerre, Isabelle

AU - Fazzi, Elisa

AU - Garcia-Cazorla, Angels

AU - Heiberg, Arvid

AU - Kawaguchi, Masakazu

AU - Kumar, Ram

AU - Lin, Jean-Pierre S-M

AU - Lourenco, Charles M

AU - Male, Alison M

AU - Marques, Wilson

AU - Mignot, Cyril

AU - Olivieri, Ivana

AU - Orcesi, Simona

AU - Prabhakar, Prab

AU - Rasmussen, Magnhild

AU - Robinson, Robert A

AU - Rozenberg, Flore

AU - Schmidt, Johanna L

AU - Steindl, Katharina

AU - Tan, Tiong Y

AU - van der Merwe, William G

AU - Vanderver, Adeline

AU - Vassallo, Grace

AU - Wakeling, Emma L

AU - Wassmer, Evangeline

AU - Whittaker, Elizabeth

AU - Livingston, John H

AU - Lebon, Pierre

AU - Suzuki, Tamio

AU - McLaughlin, Paul J

AU - Keegan, Liam P

AU - O'Connell, Mary A

AU - Lovell, Simon C

AU - Crow, Yanick J

PY - 2012/11

Y1 - 2012/11

N2 - Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

AB - Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

KW - Adenosine Deaminase

KW - Alu Elements

KW - Animals

KW - Autoimmune Diseases of the Nervous System

KW - Exome

KW - Gene Expression

KW - Humans

KW - Interferon Type I

KW - Mice

KW - Mutation

KW - Nervous System Malformations

KW - Protein Conformation

KW - RNA, Double-Stranded

KW - Sequence Analysis, DNA

KW - Signal Transduction

KW - Structure-Activity Relationship

UR - http://hdl.handle.net/2160/12777

U2 - 10.1038/ng.2414

DO - 10.1038/ng.2414

M3 - Article

C2 - 23001123

SN - 1061-4036

VL - 44

SP - 1243

EP - 1248

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

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