Ciliopathy disease gene identification by whole exome medical resequencing

全外显子组医学重测序鉴定纤毛病疾病基因

• 批准号: MR/K011154/1
• 负责人: Colin Johnson
• 金额: $ 60.87万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK011154%2F1
• 关键词: Ciliopathy; disease; gene; identification; whole

Cilia are finger-like projections from cells that act as a cellular "antenna" to detect and respond to chemical or mechanical cues. One important cue is fluid flow during the process of establishing asymmetry during early embryogenesis, the formation of the kidney nephron, and the formation of other tubular structures such as the neural tube. A group of comparatively common inherited conditions called "ciliopathies" can arise when the structure or function of cilia are defective. For example, cystic kidney disease is a common feature of many ciliopathies, often leads to kidney failure, and is therefore a significant cause of childhood disease and death. The most severe ciliopathy ("Meckel-Gruber syndrome") also involves problems in the development of the brain and spinal cord (called "neural tube defects") that arise during growth of babies in the womb. Reduced or absent mucus clearance from the lungs is the main consequence in other ciliopathies ("primary ciliary dyskinesia"), which causes recurrent respiratory infections and progressive damage to the respiratory system. In many ciliopathies, there are disturbances in the patterns of left-right organization of the lungs and heart, which are also seen in congenital heart defects (CHD), the most common birth defect.This research proposes to identify many of the remaining disease genes that are defective ("mutated") in this group of ciliopathies. To achieve this aim, we will take advantage of recent exciting advances in genetic technology that allow us to analyze the entire coding parts of a patient's genome ("whole exome sequencing"). We are uniquely placed to do this work and have a proven track record of success in this field: we have formed excellent research partnerships with families and their clinicians in the local community to participate in gene identification studies, and we have the appropriate state-of-the-art technology, computer analysis tools and experience.The identification of a new ciliopathy gene provides two major benefits. Firstly, accurate genetic testing then becomes possible for patients and families, with improvements in diagnosis and genetic counselling. Secondly, important and often unexpected scientific insights are made into the disease mechanism of the ciliopathy and into the normal function of the disease gene, which can lead to new treatments. We also expect new insights into the causes of other, more common conditions such as polycystic kidney disease, spina bifida and congenital heart defects.

纤毛是细胞的手指状突起，充当细胞的“天线”，探测和响应化学或机械信号。一个重要的线索是在早期胚胎发生、肾脏肾元的形成和其他管状结构（如神经管）的形成过程中建立不对称的流体流动。当纤毛的结构或功能有缺陷时，一组比较常见的遗传性疾病被称为“纤毛病”。例如，囊性肾病是许多纤毛病的共同特征，经常导致肾衰竭，因此是儿童疾病和死亡的重要原因。最严重的纤毛病（“梅克尔-格鲁伯综合征”）还涉及婴儿在子宫内生长过程中出现的大脑和脊髓发育问题（称为“神经管缺陷”）。肺部粘液清除减少或缺失是其他纤毛病（“原发性纤毛运动障碍”）的主要后果，它导致反复呼吸道感染和呼吸系统的进行性损害。在许多纤毛病中，肺和心脏的左右组织模式受到干扰，这也见于最常见的出生缺陷——先天性心脏缺陷（CHD）。这项研究提出了在这组纤毛病中确定许多剩余的有缺陷的疾病基因（“突变”）。为了实现这一目标，我们将利用最近令人兴奋的基因技术进步，使我们能够分析患者基因组的整个编码部分（“全外显子组测序”）。我们在这项工作中处于独特的地位，并且在这一领域取得了成功：我们与当地社区的家庭及其临床医生建立了良好的研究伙伴关系，参与基因鉴定研究，我们拥有适当的最先进的技术，计算机分析工具和经验。新的纤毛病基因的鉴定提供了两个主要的好处。首先，随着诊断和遗传咨询的改进，对患者和家属进行准确的基因检测成为可能。其次，对纤毛病的发病机制和疾病基因的正常功能进行了重要且往往出乎意料的科学见解，从而可以导致新的治疗方法。我们还希望对其他更常见的疾病，如多囊肾病、脊柱裂和先天性心脏缺陷的病因有新的认识。

项目成果

Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.

• DOI: 10.1038/s41467-018-06448-y
• 发表时间: 2018-10-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Buskin A;Zhu L;Chichagova V;Basu B;Mozaffari-Jovin S;Dolan D;Droop A;Collin J;Bronstein R;Mehrotra S;Farkas M;Hilgen G;White K;Pan KT;Treumann A;Hallam D;Bialas K;Chung G;Mellough C;Ding Y;Krasnogor N;Przyborski S;Zwolinski S;Al-Aama J;Alharthi S;Xu Y;Wheway G;Szymanska K;McKibbin M;Inglehearn CF;Elliott DJ;Lindsay S;Ali RR;Steel DH;Armstrong L;Sernagor E;Urlaub H;Pierce E;Lührmann R;Grellscheid SN;Johnson CA;Lako M
• 通讯作者: Lako M

Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.

• DOI: 10.1136/jmedgenet-2016-104436
• 发表时间: 2017-06
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Bruel AL;Franco B;Duffourd Y;Thevenon J;Jego L;Lopez E;Deleuze JF;Doummar D;Giles RH;Johnson CA;Huynen MA;Chevrier V;Burglen L;Morleo M;Desguerres I;Pierquin G;Doray B;Gilbert-Dussardier B;Reversade B;Steichen-Gersdorf E;Baumann C;Panigrahi I;Fargeot-Espaliat A;Dieux A;David A;Goldenberg A;Bongers E;Gaillard D;Argente J;Aral B;Gigot N;St-Onge J;Birnbaum D;Phadke SR;Cormier-Daire V;Eguether T;Pazour GJ;Herranz-Pérez V;Goldstein JS;Pasquier L;Loget P;Saunier S;Mégarbané A;Rosnet O;Leroux MR;Wallingford JB;Blacque OE;Nachury MV;Attie-Bitach T;Rivière JB;Faivre L;Thauvin-Robinet C
• 通讯作者: Thauvin-Robinet C

DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.

• DOI: 10.1093/hmg/ddx422
• 发表时间: 2018-02-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Hartill VL;van de Hoek G;Patel MP;Little R;Watson CM;Berry IR;Shoemark A;Abdelmottaleb D;Parkes E;Bacchelli C;Szymanska K;Knoers NV;Scambler PJ;Ueffing M;Boldt K;Yates R;Winyard PJ;Adler B;Moya E;Hattingh L;Shenoy A;Hogg C;Sheridan E;Roepman R;Norris D;Mitchison HM;Giles RH;Johnson CA
• 通讯作者: Johnson CA

Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances.

• DOI: 10.3389/fped.2017.00244
• 发表时间: 2017
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Hartill V;Szymanska K;Sharif SM;Wheway G;Johnson CA
• 通讯作者: Johnson CA

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

剪接体基因PPIL1和PRP17中的突变引起神经退行性pontocerebellar垂体性发育不全。

• DOI: 10.1016/j.neuron.2020.10.035
• 发表时间: 2021-01-20
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Chai G;Webb A;Li C;Antaki D;Lee S;Breuss MW;Lang N;Stanley V;Anzenberg P;Yang X;Marshall T;Gaffney P;Wierenga KJ;Chung BH;Tsang MH;Pais LS;Lovgren AK;VanNoy GE;Rehm HL;Mirzaa G;Leon E;Diaz J;Neumann A;Kalverda AP;Manfield IW;Parry DA;Logan CV;Johnson CA;Bonthron DT;Valleley EMA;Issa MY;Abdel-Ghafar SF;Abdel-Hamid MS;Jennings P;Zaki MS;Sheridan E;Gleeson JG
• 通讯作者: Gleeson JG