Alport syndrome is an inherited disorder characterized by kidney disease, sensorineural hearing loss, and ocular abnormalities. Alport syndrome is caused by pathogenic variants in COL4A3 , COL4A4 , or COL4A5 , which encode the α 3, α 4, and α 5 chains of type 4 collagen that forms a heterotrimer expressed in the glomerular basement membrane. Knowledge of its genetic basis has informed the development of different models in dogs, mice, and rats that reflect its autosomal and X-linked inheritance patterns as well as different mutation types, including protein-truncating and missense variants. A key difference between these two types is the synthesis of α 3 α 4 α 5(IV), which is not made in autosomal Alport syndrome (two pathogenic variants in trans or biallelic) or male patients with X-linked Alport syndrome due to protein-truncating variants. By contrast, α 3 α 4 α 5(IV) is synthesized in Alport syndrome because of missense variants. For missense variants, in vitro studies suggest that these cause impaired type 4 collagen trafficking and endoplasmic reticulum stress. For protein-truncating variants, knockout models suggest that persistence of an immature α 1 α 1 α 2(IV) network is associated with biomechanical strain, which activates endothelin-A receptors leading to mesangial filopodia formation. Moreover, studies suggest that activation of collagen receptors, integrins and discoidin domain receptor 1, play a role in disease propagation. In this review, we provide an overview of how these genotype-phenotype mechanisms are key for a precision medicine-based approach in the future.

中文翻译：

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Alport 综合征中基于基因型的分子机制。


Alport 综合征是一种遗传性疾病，其特征是肾脏疾病、感音神经性听力损失和眼部异常。Alport 综合征是由 COL4A3 、 COL4A4 或 COL4A5 的致病性变异引起的，这些变异编码 4 型胶原蛋白的 α 3、α 4 和 α 5 链，形成在肾小球基底膜中表达的异源三聚体。对其遗传基础的了解为狗、小鼠和大鼠不同模型的开发提供了信息，这些模型反映了其常染色体和 X 连锁遗传模式以及不同的突变类型，包括蛋白质截短和错义变体。这两种类型的一个关键区别是 α 3 α 4 α 5（IV） 的合成，它不是在常染色体 Alport 综合征（反式或双等位基因的两种致病性变异）或由于蛋白质截短变异而患有 X 连锁 Alport 综合征的男性患者中产生的。相比之下，由于错义变异，α 3 α 4 α 5（IV） 是在 Alport 综合征中合成的。对于错义变异，体外研究表明，这些变异会导致 4 型胶原蛋白运输受损和内质网应激。对于蛋白质截短变体，敲除模型表明，未成熟α 1 α 1 α 2（IV） 网络的持续存在与生物力学应变有关，生物力学应变激活内皮素 A 受体，导致系膜丝状伪足形成。此外，研究表明，胶原受体、整合素和盘状蛋白结构域受体 1 的激活在疾病传播中发挥作用。在这篇综述中，我们概述了这些基因型-表型机制如何成为未来基于精准医学的方法的关键。