Alagille Syndrome: Unraveling the Complexities of Genotype–Phenotype Relationships and Exploring Avenues for Improved Diagnosis and Treatment

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Priya Sharma, Deepti Abbey
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引用次数: 0

Abstract

Alagille syndrome (ALGS) is a rare genetic disorder caused by mutations in the JAG1 and NOTCH2 genes, leading to a wide range of clinical manifestations. This review explores the complex genetic and clinical landscape of ALGS, emphasizing the challenges in understanding genotype-phenotype relationships due to its rarity and the lack of suitable research models. The review projects a clinical overview of the disease, emphasizing the influence of potential gene modifiers on its clinical presentation and the lack of mechanistic studies for over 100 mutations identified in the last 24 years from various populations, representing a significant gap in our current knowledge and advocating for further exploration. The review addresses the diagnostic challenges posed by the variable expressivity and overlapping symptoms of ALGS. It summarizes current treatment options and discusses emerging approaches such as antisense oligonucleotides (ASOs) and gene therapies. Further, the need for improved diagnostic tools, a deeper understanding of the underlying mechanisms, and the development of targeted therapies are emphasized using zebrafish and mice models, as well as genome editing for variant analysis and stem cell organoid models for disease modeling and drug discovery. The importance of cohort-based studies in understanding the natural history and outcomes of ALGS in diverse populations is highlighted. The review concludes by emphasizing the need for multi-disciplinary collaborative research to address the challenges in ALGS diagnosis, prognosis, and treatment, particularly for underrepresented populations.

阿拉吉尔综合征:揭示基因型-表型关系的复杂性,探索改善诊断和治疗的途径。
Alagille综合征(ALGS)是一种罕见的由JAG1和NOTCH2基因突变引起的遗传性疾病,临床表现广泛。这篇综述探讨了ALGS复杂的遗传和临床情况,强调了由于其罕见性和缺乏合适的研究模型,在理解基因型-表型关系方面的挑战。该综述概述了该疾病的临床概况,强调了潜在基因修饰剂对其临床表现的影响,以及在过去24年中从不同人群中发现的100多个突变缺乏机制研究,这表明我们目前的知识存在重大差距,并提倡进一步探索。本综述探讨了ALGS的可变表达性和重叠症状所带来的诊断挑战。它总结了目前的治疗方案,并讨论了新兴的方法,如反义寡核苷酸(ASOs)和基因治疗。此外,还强调需要改进诊断工具,更深入地了解潜在机制,并使用斑马鱼和小鼠模型开发靶向治疗,以及用于变异分析的基因组编辑和用于疾病建模和药物发现的干细胞类器官模型。强调了基于队列的研究在了解不同人群ALGS的自然历史和结果方面的重要性。该综述最后强调需要进行多学科合作研究,以解决ALGS诊断、预后和治疗方面的挑战,特别是对代表性不足的人群。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
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