From Microcephaly to Genome Stability,Inflammation and Growth Regulation

从小头畸形到基因组稳定性、炎症和生长调节

• 批准号: MC_UU_00007/5
• 负责人: Andrew Jackson
• 金额: $ 576.45万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00007%2F5
• 关键词: Microcephaly; Genome; Stability; Inflammation; Growth

This research programme identifies new genes for inherited disorders affecting the human brain. We also study how these genes function using cells and model organisms. Aicardi-Goutières syndrome is a genetic condition in which faults in genes encoding enzymes called nucleases, mimic viral infection of the brain. These nucleases may normally clean up naturally produced ‘waste’ DNA and RNA, with failure of this process leading to the body mounting an immune reaction against itself. This immune response mechanism is relevant to common autoimmune diseases such as lupus and so we are studying these enzymes to understand their normal roles in cells and to establish what happens when these enzymes fail.Secondly, we are identifying genes that cause extreme growth failure of the brain and body. Individuals with primordial dwarfism are often described as the 'smallest people in the world'. These genes are components of the core cell machinery which controls cell duplication and mutations likely result in fewer cells being made, leading to a smaller person. Identifying these genes will help diagnosis and management of these rare conditions. It may also help us better understand how the body regulates growth, perhaps shedding light into why humans are bigger than mice and how our brains evolved to be so large.

这项研究计划确定了影响人类大脑的遗传性疾病的新基因。我们还研究了这些基因如何使用细胞和模式生物的功能。Aicardi-Goutières综合征是一种遗传性疾病，其中编码核酸酶的基因中存在缺陷，模拟大脑的病毒感染。这些核酸酶通常可以清除自然产生的“废物”DNA和RNA，这一过程的失败会导致身体产生针对自身的免疫反应。这种免疫反应机制与常见的自身免疫性疾病（如狼疮）有关，因此我们正在研究这些酶，以了解它们在细胞中的正常作用，并确定当这些酶失效时会发生什么。其次，我们正在识别导致大脑和身体极度生长障碍的基因。患有原始侏儒症的人通常被描述为“世界上最小的人”。这些基因是控制细胞复制和突变的核心细胞机制的组成部分，可能会导致更少的细胞被制造，导致更小的人。识别这些基因将有助于诊断和管理这些罕见疾病。它还可能帮助我们更好地了解身体如何调节生长，也许可以解释为什么人类比老鼠大，以及我们的大脑是如何进化到如此之大的。

项目成果

RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition.

在Aicardi-Goutières综合征中突变的RNase H2促进了LINE-1逆转录位。

• DOI: 10.15252/embj.201798506
• 发表时间: 2018-08-01
• 期刊: The EMBO journal
• 作者: Benitez-Guijarro M;Lopez-Ruiz C;Tarnauskaitė Ž;Murina O;Mian Mohammad M;Williams TC;Fluteau A;Sanchez L;Vilar-Astasio R;Garcia-Canadas M;Cano D;Kempen MH;Sanchez-Pozo A;Heras SR;Jackson AP;Reijns MA;Garcia-Perez JL
• 通讯作者: Garcia-Perez JL

The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome.

• DOI: 10.1002/ajmg.a.38581
• 发表时间: 2018-03
• 期刊: American journal of medical genetics. Part A
• 作者: Farach LS;Little ME;Duker AL;Logan CV;Jackson A;Hecht JT;Bober M
• 通讯作者: Bober M

Microcephalic Osteodysplastic Primordial Dwarfism Type II

小头骨发育不良原始侏儒症 II 型

• 发表时间: 2021
• 期刊: GeneReviews
• 作者: Duker A

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes.

• DOI: 10.1084/jem.20211121
• 发表时间: 2022-04-04
• 期刊: The Journal of experimental medicine
• 作者: Giordano AMS;Luciani M;Gatto F;Abou Alezz M;Beghè C;Della Volpe L;Migliara A;Valsoni S;Genua M;Dzieciatkowska M;Frati G;Tahraoui-Bories J;Giliani SC;Orcesi S;Fazzi E;Ostuni R;D'Alessandro A;Di Micco R;Merelli I;Lombardo A;Reijns MAM;Gromak N;Gritti A;Kajaste-Rudnitski A
• 通讯作者: Kajaste-Rudnitski A

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

• DOI: 10.1038/s41467-022-34349-8
• 发表时间: 2022-11-04
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Grange, Laura J.;Reynolds, John J.;Ullah, Farid;Isidor, Bertrand;Shearer, Robert F.;Latypova, Xenia;Baxley, Ryan M.;Oliver, Antony W.;Ganesh, Anil;Cooke, Sophie L.;Jhujh, Satpal S.;McNee, Gavin S.;Hollingworth, Robert;Higgs, Martin R.;Natsume, Toyoaki;Khan, Tahir;Martos-Moreno, Gabriel A.;Chupp, Sharon;Mathew, Christopher G.;Parry, David;Simpson, Michael A.;Nahavandi, Nahid;Yuksel, Zafer;Drasdo, Mojgan;Kron, Anja;Vogt, Petra;Jonasson, Annemarie;Seth, Saad Ahmed;Gonzaga-Jauregui, Claudia;Brigatti, Karlla W.;Stegmann, Alexander P. A.;Kanemaki, Masato;Josifova, Dragana;Uchiyama, Yuri;Oh, Yukiko;Morimoto, Akira;Osaka, Hitoshi;Ammous, Zineb;Argente, Jesus;Matsumoto, Naomichi;Stumpel, Constance T. R. M.;Taylor, Alexander M. R.;Jackson, Andrew P.;Bielinsky, Anja-Katrin;Mailand, Niels;Le Caignec, Cedric;Davis, Erica E.;Stewart, Grant S.
• 通讯作者: Stewart, Grant S.