RASopathies: unraveling mechanisms with animal models.
RASopathies: unraveling mechanisms with animal models.
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DOI：
10.1242/dmm.020339
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发表时间：
2015-08-01
影响因子：
4.3
通讯作者：
Shvartsman SY
中科院分区：
文献类型：
--
作者：
Jindal GA;Goyal Y;Burdine RD;Rauen KA;Shvartsman SY
RASopathies 是由 Ras-MAPK 途径种系突变引起的发育障碍，其特征是广泛的功能和形态异常。这些疾病的高发病率（约 1/1000 的出生率）促进了系统方法的开发，以实现其有效的诊断和潜在的治疗。基因组测序的最新进展极大地促进了受影响个体的基因分型和突变发现，但建立分子和疾病表型之间的因果关系并非易事，并且提出了技术和概念上的挑战。在这里，我们讨论如何使用转基因模型生物体来解决这些挑战，这些生物体有助于描述 Ras-MAPK 通路及其在发育过程中的作用。我们重点关注小鼠、斑马鱼和果蝇的研究，在分子和功能水平上对 RASopathies 动物模型进行最新综述。我们还讨论了如何使用日益复杂的基因工程技术将 Ras-MAPK 途径特定成分的变化与观察到的功能和形态表型严格联系起来。建立这些联系对于增进我们对 RASopathies 的理解以及为其管理和治疗制定合理的策略至关重要。摘要：由 Ras-MAPK 途径种系突变引起的发育障碍称为 RASopathies。对小鼠、斑马鱼和果蝇等动物模型的研究不断加深我们对这些疾病的了解。
RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. Summary: Developmental disorders caused by germline mutations in the Ras-MAPK pathway are called RASopathies. Studies with animal models, including mice, zebrafish and Drosophila, continue to enhance our understanding of these diseases.