Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
复制标题
DOI：
10.1002/ajmg.a.36887
复制
发表时间：
2015-02
影响因子：
2
通讯作者：
Rice, Gillian I.
中科院分区：
文献类型：
--
作者：
Crow, Yanick J.;Chase, Diana S.;Schmidt, Johanna Lowenstein;Szynkiewicz, Marcin;Forte, Gabriella M. A.;Gornall, Hannah L.;Oojageer, Anthony;Anderson, Beverley;Pizzino, Amy;Helman, Guy;Abdel-Hamid, Mohamed S.;Abdel-Salam, Ghada M.;Ackroyd, Sam;Aeby, Alec;Agosta, Guillermo;Albin, Catherine;Allon-Shalev, Stavit;Arellano, Montse;Ariaudo, Giada;Aswani, Vijay;Babul-Hirji, Riyana;Baildam, Eileen M.;Bahi-Buisson, Nadia;Bailey, Kathryn M.;Barnerias, Christine;Barth, Magalie;Battini, Roberta;Beresford, Michael W.;Bernard, Genevieve;Bianchi, Marika;de Villemeur, Thierry Billette;Blair, Edward M.;Bloom, Miriam;Burlina, Alberto B.;Carpanelli, Maria Luisa;Carvalho, Daniel R.;Castro-Gago, Manuel;Cavallini, Anna;Cereda, Cristina;Chandler, Kate E.;Chitayat, David A.;Collins, Abigail E.;Sierra Corcoles, Concepcion;Cordeiro, Nuno J. V.;Crichiutti, Giovanni;Dabydeen, Lyvia;Dale, Russell C.;D'Arrigo, Stefano;De Goede, Christian G. E. L.;De Laet, Corinne;De Waele, Liesbeth M. H.;Denzler, Ines;Desguerre, Isabelle;Devriendt, Koenraad;Di Rocco, Maja;Fahey, Michael C.;Fazzi, Elisa;Ferrie, Colin D.;Figueiredo, Antonio;Gener, Blanca;Goizet, Cyril;Gowrinathan, Nirmala R.;Gowrishankar, Kalpana;Hanrahan, Donncha;Isidor, Bertrand;Kara, Lent;Khan, Nasaim;King, Mary D.;Kirk, Edwin P.;Kumar, Ram;Lagae, Lieven;Landrieu, Pierre;Lauffer, Heinz;Laugel, Vincent;La Piana, Roberta;Lim, Ming J.;Lin, Jean-Pierre S. -M.;Linnankivi, Tarja;Mackay, Mark T.;Marom, Daphna R.;Lourenco, Charles Marques;McKee, Shane A.;Moroni, Isabella;Morton, Jenny E. V.;Moutard, Marie-Laure;Murray, Kevin;Nabbout, Rima;Nampoothiri, Sheela;Nunez-Enamorado, Noemi;Oades, Patrick J.;Olivieri, Ivana;Ostergaard, John R.;Perez-Duenas, Belen;Prendiville, Julie S.;Ramesh, Venkateswaran;Rasmussen, Magnhild;Regal, Luc;Ricci, Federica;Rio, Marlene;Rodriguez, Diana;Roubertie, Agathe;Salvatici, Elisabetta;Segers, Karin A.;Sinha, Gyanranjan P.;Soler, Doriette;Spiegel, Ronen;Stoedberg, Tommy I.;Straussberg, Rachel;Swoboda, Kathryn J.;Suri, Mohnish;Tacke, Uta;Tan, Tiong Y.;Naude, Johann te Water;Teik, Keng Wee;Thomas, Maya Mary;Till, Marianne;Tonduti, Davide;Valente, Enza Maria;Van Coster, Rudy Noel;van der Knaap, Marjo S.;Vassallo, Grace;Vijzelaar, Raymon;Vogt, Julie;Wallace, Geoffrey B.;Wassmer, Evangeline;Webb, Hannah J.;Whitehouse, William P.;Whitney, Robyn N.;Zaki, Maha S.;Zuberi, Sameer M.;Livingston, John H.;Rozenberg, Flore;Lebon, Pierre;Vanderver, Adeline;Orcesi, Simona;Rice, Gillian I.
关键词：
艾卡迪-古蒂埃综合征是一种炎症性疾病，由TREX1、RNASE H 2A、RNASE H 2B、RNASE H 2C、SAMHD1、ADAR或IFIH1中的任何一个突变引起。我们报告了来自299个家系的374名患者的这七个基因突变。大多数患者符合两种相当刻板的临床特征之一；要么表现为宫内发病(74例；占所有可获得数据的患者的22.8%)，要么表现为产后表现，通常在出生后一年内(223例；68.6%)，特征是亚急性脑病和先前获得的技能丧失。还观察到了其他临床上不同的表型，特别是双侧纹状体坏死(13例；3.6%)和非综合征性痉挛瘫痪(12例，3.4%)。我们记录了69例死亡(19.3%的患者有随访数据)。在可获得数据的285名患者中，210名(73.7%)严重残疾，没有有用的运动、语言和智力功能。冻疮、青光眼、甲状腺功能减退症、心肌病、脑血管炎、周围神经病变、肠道炎症和系统性红斑狼疮的出现频率足够高，足以被证实与艾卡迪-古蒂埃综合征表型有关。我们观察到，所有七个基因的突变与脑脊液和血清中I型干扰素活性的增加以及干扰素刺激的基因转录产物在外周血中的表达增加之间存在强烈的相关性。我们记录了在疾病出现一年内检测的脑脊液干扰素活性水平与随后的残疾程度之间的正相关关系。在大多数患者中，干扰素刺激的基因转录保持在较高水平，表明疾病过程正在进行。在相当高的发病率和死亡率的基础上，我们的数据突出表明，迫切需要为与艾卡迪-古蒂埃综合征相关基因突变相关的表型确定一致的治疗策略。我们的发现也清楚地表明，与大多数受影响的患者相关的治疗机会之窗存在，并表明I型干扰素活性的评估可能在未来的临床试验中作为一个有用的生物标记物。
Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
登录
查看更多内容
从DNA中酶促去除核糖核苷酸对于哺乳动物的基因组完整性和发育至关重要。
影响因子：
64.5
作者：
Reijns MA;Rabe B;Rigby RE;Mill P;Astell KR;Lettice LA;Boyle S;Leitch A;Keighren M;Kilanowski F;Devenney PS;Sexton D;Grimes G;Holt IJ;Hill RE;Taylor MS;Lawson KA;Dorin JR;Jackson AP
通讯作者：
Jackson AP
影响因子：
--
作者：
Barizzone, Nadia;Monti, Sara;D'Alfonso, Sandra
通讯作者：
D'Alfonso, Sandra
影响因子：
30.8
作者：
Crow, Yanick J.;Leitch, Andrea;Jackson, Andrew P.
通讯作者：
Jackson, Andrew P.
DOI：
10.1111/j.1749-6632.2011.06220.x
发表时间：
2011-01-01
期刊：
YEAR IN HUMAN AND MEDICAL GENETICS: INBORN ERRORS OF IMMUNITY I
影响因子：
--
作者：
Crow, Yanick J.
通讯作者：
Crow, Yanick J.
DOI：
10.1111/j.1469-8749.2010.03727.x
发表时间：
2010-08-01
影响因子：
3.8
作者：
Ramesh, Venkateswaran;Bernardi, Bruno;Crow, Yanick J.
通讯作者：
Crow, Yanick J.