Genetic variation in the membrane trafficking adapter protein complex 4 (AP-4) can result in pathogenic neurological phenotypes including microencephaly, spastic paraplegias, epilepsy, and other developmental defects. We lack molecular mechanisms responsible for impaired AP-4 function arising from genetic variation, because AP-4 remains poorly understood structurally. Here, we analyze patterns of AP-4 genetic evolution and conservation to identify regions that are likely important for function and thus more susceptible to pathogenic variation. We map known variants onto an AP-4 homology model and predict the likelihood of pathogenic variation at a given location on the structure of AP-4. We find significant clustering of likely pathogenic variants located at the interface between the β4 and N-μ4 subunits, as well as throughout the C-μ4 subunit. Our work offers an integrated perspective on how genetic and evolutionary forces affect AP-4 structure and function. As more individuals with uncharacterized AP-4 variants are identified, our work provides a foundation upon which their functional effects and disease relevance can be interpreted.

中文翻译：

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整合结构和进化数据以解释衔接子蛋白复合物4的变异和致病性

膜运输衔接蛋白复合物4（AP-4）的遗传变异可导致致病性神经学表型，包括微脑残，痉挛性截瘫，癫痫和其他发育缺陷。我们缺乏导致遗传变异导致AP-4功能受损的分子机制，因为AP-4在结构上仍然知之甚少。在这里，我们分析了AP-4遗传进化和保护的模式，以识别可能对功能很重要的区域，因此更容易引起病原体变异。我们将已知变体映射到AP-4同源性模型上，并预测在AP-4结构上给定位置的病原体变异的可能性。我们发现位于β4和N-μ4亚基之间以及整个C-μ4亚基之间的界面上可能存在的致病变体明显聚集。我们的工作为遗传和进化力如何影响AP-4的结构和功能提供了一个综合的观点。随着更多具有AP-4变异特征的个体被发现，我们的工作为他们的功能作用和疾病相关性的解释奠定了基础。