Deep phenotyping to improve understanding of causal mechanisms and underlying gene mutations in primary lymphoedema and lymphatic malformations

深度表型分析可提高对原发性淋巴水肿和淋巴管畸形的因果机制和潜在基因突变的理解

• 批准号: MR/P011543/1
• 负责人: Peter Mortimer
• 金额: $ 257.22万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011543%2F1
• 关键词: Deep; phenotyping; improve; understanding; causal

Lymphoedema is swelling of any body part caused by a fault or obstruction in the lymphatic system, and is one of the most neglected areas in healthcare. Data suggest it is twice as common as type 1 diabetes (which is estimated at 400,000 in the UK) but much less recognised. Primary lymphoedema is often considered genetic in origin, whereas secondary lymphoedema has an identifiable cause such as the surgical removal of lymph glands for cancer. In the last 5 years a number of genes have been identified which, when faulty, cause inherited forms of lymphoedema. Finding the causal gene means a specific diagnosis can be made by a blood test through examination of the DNA of the patient suspected of having that particular type of lymphoedema. This helps inform the patient about their condition and what might happen to them in their lifetime. We have been studying lymphoedema for over 30 years. Genes have been discovered through investigating the DNA of patients who have as closely matched lymphoedema as it is possible to test. Detailed clinical histories and examination findings are recorded but clinical appearances alone are often not sufficient to distinguish one type of Primary Lymphoedema from another. This proposed research study is designed to provide better methods of investigation that will help distinguish one type of Primary Lymphoedema from another and give us a better insight into the mechanisms that produce the lymphoedema (and so help to design new treatments). Current tools for investigation of lymphoedema are very limited. Lymphoscintigraphy is the only widely available method within the NHS for the diagnosis of lymphoedema but it does not enable direct visualisation of the lymph vessels. Two methods are proposed to overcome this. The first is Magnetic Resonance Lymphangiography (MRL) using injected contrast, which enables distinction of lymph vessels from blood vessels. MRL will also be used to see the malformed lymph vessels inside the body. The second method of investigation is Indocyanine Green Lymphography (ICGL). This involves the injection of a dye that is seen by a camera in the near infrared spectrum wavelength of light. ICGL has been used to image lymph vessels just under the skin of an arm or leg prior to lymphatic microsurgery but has never been used to study Primary Lymphoedema. MRL will enable imaging of deeper lymph vessels whereas ICGL will provide information on lymph vessel pumping and valve function. Unlike lymphoscintigraphy neither MRL nor ICGL involve radiation. To study the smaller lymph capillaries in the skin we will perform biopsies but analyse them using a revolutionary, state of the art, 3D imaging technique. This will tell us much more about the structure and function of malfunctioning small lymphatic vessels in the patient groups. Infection can be a devastating consequence of lymphoedema because the lymph system is part of our immune system, so when the lymph system goes wrong so does immune function. We have already shown that in some genetic forms of lymphoedema, the white cells of the lymph system (lymphocytes) are low in number. There are virtually no studies in humans to explain why this is. We plan to study the numbers, trafficking and function of lymphocytes in order to understand if the immune dysfunction is a result of the genes or secondary to disturbed movement of the cells throughout the body from the lymphoedema. By developing improved investigation techniques we will be able to categorise our patients more clearly and discover more genes and how those genes make the lymph system grow and work. This may have relevance to diseases other than lymphoedema, which hitherto may not have been known to have a lymphatic contribution; for example the recovery of cardiac muscle after a heart attack may be dependent on lymphatic function. Discovering genes in primary lymphoedema will inform on their wide-ranging roles in human biology and pathology.

淋巴水肿是由淋巴系统中的故障或阻塞引起的任何身体部位的肿胀，并且是医疗保健中最被忽视的领域之一。数据显示，它是1型糖尿病（在英国估计有40万人）的两倍，但认识要少得多。原发性淋巴水肿通常被认为是遗传性的，而继发性淋巴水肿则有一个可识别的原因，例如因癌症而手术切除淋巴腺。在过去的5年中，已经确定了一些基因，当有缺陷时，会导致遗传性淋巴水肿。找到致病基因意味着可以通过血液测试通过检查怀疑患有特定类型淋巴水肿的患者的DNA来做出特定诊断。这有助于告知患者他们的病情以及他们一生中可能发生的事情。 我们已经研究淋巴水肿30多年了。通过研究淋巴水肿患者的DNA发现了基因，这些患者具有尽可能匹配的淋巴水肿。详细的临床病史和检查结果被记录下来，但仅凭临床表现往往不足以区分一种类型的原发性脑水肿。这项拟议的研究旨在提供更好的调查方法，有助于区分一种类型的原发性淋巴水肿，并使我们更好地了解产生淋巴水肿的机制（从而有助于设计新的治疗方法）。 目前研究淋巴水肿的工具非常有限。淋巴管造影术是NHS内唯一广泛使用的诊断淋巴水肿的方法，但它不能直接显示淋巴管。提出了两种方法来克服这个问题。第一种是使用注射造影剂的磁共振淋巴管造影术（MRL），它可以区分淋巴管和血管。MRL也将用于查看体内畸形的淋巴管。第二种研究方法是吲哚菁绿色照相法（ICGL）。这涉及到注入一种染料，这种染料在近红外光谱波长的光中被相机看到。ICGL已被用于在淋巴显微手术之前对手臂或腿部皮肤下的淋巴管进行成像，但从未用于研究原发性淋巴水肿。MRL将使更深的淋巴管成像，而ICGL将提供有关淋巴管泵和瓣膜功能的信息。与淋巴结造影术不同，MRL和ICGL均不涉及辐射。 为了研究皮肤中较小的淋巴毛细血管，我们将进行活检，但使用革命性的最先进的3D成像技术进行分析。这将告诉我们更多关于患者组中功能失调的小淋巴管的结构和功能。 感染可能是淋巴水肿的毁灭性后果，因为淋巴系统是我们免疫系统的一部分，所以当淋巴系统出错时，免疫功能也会发生变化。我们已经指出，在某些遗传性淋巴水肿中，淋巴系统的白色细胞（淋巴细胞）数量较少。几乎没有人类研究来解释为什么会这样。我们计划研究淋巴细胞的数量，运输和功能，以了解免疫功能障碍是基因的结果还是继发于淋巴水肿引起的全身细胞运动紊乱。 通过开发改进的研究技术，我们将能够更清楚地对患者进行分类，并发现更多的基因以及这些基因如何使淋巴系统生长和工作。这可能与淋巴水肿以外的疾病有关，迄今为止可能还不知道淋巴水肿有淋巴贡献;例如，心脏病发作后心肌的恢复可能取决于淋巴功能。发现原发性淋巴水肿的基因将告知其在人类生物学和病理学中的广泛作用。

项目成果

Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts.

• DOI: 10.1136/jmedgenet-2021-107820
• 发表时间: 2023-01
• 期刊: Journal of medical genetics
• 影响因子: 4

The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.

• DOI: 10.1002/ajmg.a.62716
• 发表时间: 2022-06
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Kontaridis, Maria, I;Roberts, Amy E.;Schill, Lisa;Schoyer, Lisa;Stronach, Beth;Andelfinger, Gregor;Aoki, Yoko;Axelrad, Marni E.;Bakker, Annette;Bennett, Anton M.;Broniscer, Alberto;Castel, Pau;Chang, Caitlin A.;Cyganek, Lukas;Das, Tirtha K.;den Hertog, Jeroen;Galperin, Emilia;Garg, Shruti;Gelb, Bruce D.;Gordon, Kristiana;Green, Tamar;Gripp, Karen W.;Itkin, Maxim;Kiuru, Maija;Korf, Bruce R.;Livingstone, Jeff R.;Lopez-Juarez, Alejandro;Magoulas, Pilar L.;Mansour, Sahar;Milner, Theresa;Parker, Elisabeth;Pierpont, Elizabeth, I;Plouffe, Kevin;Rauen, Katherine A.;Shankar, Suma P.;Smith, Shane B.;Stevenson, David A.;Tartaglia, Marco;Van, Richard;Wagner, Morgan E.;Ware, Stephanie M.;Zenker, Martin
• 通讯作者: Zenker, Martin

Genetic association analysis of 77,539 genomes reveals rare disease etiologies.

• DOI: 10.1038/s41591-023-02211-z
• 发表时间: 2023-03
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Greene, Daniel;Pirri, Daniela;Frudd, Karen;Sackey, Ege;Al-Owain, Mohammed;Giese, Arnaud P. J.;Ramzan, Khushnooda;Riaz, Sehar;Yamanaka, Itaru;Boeckx, Nele;Thys, Chantal;Gelb, Bruce D.;Brennan, Paul;Hartill, Verity;Harvengt, Julie;Kosho, Tomoki;Mansour, Sahar;Masuno, Mitsuo;Ohata, Takako;Stewart, Helen;Taibah, Khalid;Turner, Claire L. S.;Imtiaz, Faiqa;Riazuddin, Saima;Morisaki, Takayuki;Ostergaard, Pia;Loeys, Bart L.;Morisaki, Hiroko;Ahmed, Zubair M.;Birdsey, Graeme M.;Freson, Kathleen;Mumford, Andrew;Turro, Ernest
• 通讯作者: Turro, Ernest

Handbook of Skin Disease Management

皮肤病管理手册

• 发表时间: 2023
• 作者: Jiyad

Update and audit of the St George's classification algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis.

• DOI: 10.1136/jmedgenet-2019-106084
• 发表时间: 2020-10
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Gordon K;Varney R;Keeley V;Riches K;Jeffery S;Van Zanten M;Mortimer P;Ostergaard P;Mansour S
• 通讯作者: Mansour S