Mantoan Ritter Laura, Annear Nicholas M P, Baple Emma L, Ben-Chaabane Leila Y, Bodi Istvan, Brosson Lauren, Cadwgan Jill E, Coslett Bryn, Crosby Andrew H, Davies D Mark, Daykin Nicola, Dedeurwaerdere Stefanie, Dühring Fenger Christina, Dunlop Elaine A, Elmslie Frances V, Girodengo Marie, Hambleton Sophie, Jansen Anna C, Johnson Simon R, Kearley Kelly C, Kingswood John C, Laaniste Liisi, Lachlan Katherine, Latchford Andrew, Madsen Ralitsa R, Mansour Sahar, Mihaylov Simeon R, Muhammed Louwai, Oliver Claire, Pepper Tom, Rawlins Lettie E, Schim van der Loeff Ina, Siddiqui Ata, Takhar Pooja, Tatton-Brown Katrina, Tee Andrew R, Tibarewal Priyanka, Tye Charlotte, Ultanir Sila K, Vanhaesebroeck Bart, Zare Benjamin, Pal Deb K, Bateman Joseph M
King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK.
King's College Hospital NHS Foundation Trust, London, UK.
Orphanet J Rare Dis. 2025 May 27;20(1):256. doi: 10.1186/s13023-025-03740-1.
Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.
雷帕霉素作用机制靶点（mTOR）是一种高度保守的丝氨酸/苏氨酸激酶，可调节包括细胞生长、自噬和代谢在内的关键细胞过程。mTOR信号通路的过度激活会导致一组罕见和超罕见的遗传性疾病。mTOR信号通路疾病具有多样的临床表现，由不同的医学学科进行管理，但有着共同的潜在分子基础。目前，人们对调节mTOR信号通路的分子基础有了深入了解，但大多数mTOR信号通路疾病仍缺乏有效的治疗方法。将科学知识转化为临床应用以满足患者未得到满足的临床需求，是许多罕见病共同面临的重大挑战。在本文中，我们阐述了mTOR信号通路疾病如何提供一个机会，通过汇聚专业知识并推动进展以造福患者，来协调基础研究和转化性疾病研究，涉及研究团队、产业界、医学研究基金会、慈善机构和患者群体。我们概述了mTOR信号通路中导致罕见疾病的种系和体细胞突变，并总结了该组中每种疾病的患病率、遗传基础、临床表现、病理生理学和当前治疗方法。我们描述了在阐明潜在机制、改善诊断和预后以及开发和批准mTOR信号通路疾病新疗法方面取得进展所面临的挑战和机遇。我们说明了患者公众参与在罕见病和mTOR信号通路疾病研究中的关键作用。最后，我们解释了作为英国研究疾病研究平台一部分的mTOR信号通路疾病节点将如何应对这些挑战，以增进对mTOR信号通路疾病的理解、诊断和治疗。
