摘要

WDR45基因位于X 染色体上，该基因的变异与六种不同的神经退行性疾病有关，即 ß-螺旋桨蛋白相关的神经退行性疾病、Rett 样综合征、智力障碍和癫痫性脑病，包括发育性和癫痫性脑病、早期- 发作性癫痫性脑病和 West 综合征以及潜在的特定恶性肿瘤。WDR45/WIPI4 是一种 WD 重复 β-螺旋桨蛋白，属于 WIPI（WD 重复结构域，磷酸肌醇相互作用）家族。WDR45 的精确细胞功能仍然很大程度上未知，但WDR45中的缺失或常规变体可导致巨自噬/自噬缺陷、线粒体功能障碍、内质网应激和不平衡的铁稳态，表明该蛋白在一个或多个直接或间接调节这些过程的途径中发挥作用。因此，WDR45 相关疾病的根本原因仍然未知。在这篇综述中，我们总结了当前关于 WDR45 的细胞和生理功能的知识，并强调了其编码基因中的遗传变异如何促成相关疾病的病理生理学。特别是，我们将这些疾病的临床表现与其潜在的细胞功能障碍联系起来，并批判性地讨论最突出的共同特征之一，即脑铁积累，是否可能是这些疾病的主要原因。

缩写： ATG/Atg：自噬相关；BPAN：β-螺旋桨蛋白相关的神经变性；CNS：中枢神经系统；DEE：发育性和癫痫性脑病；EEG：脑电图；ENO2/神经元特异性烯醇化酶，烯醇化酶2；EOEE：早发性癫痫性脑病；ER：内质网；ID：智力障碍；IDR：本质上无序的区域；MRI：磁共振成像；NBIA：伴有脑铁积累的神经变性；NCOA4：核受体共激活因子 4；PtdIns3P：3-磷酸磷脂酰肌醇；RLS：雷特样综合征；WDR45：WD 重复结构域 45；WIPI：WD 重复结构域，磷酸肌醇相互作用

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ABSTRACT

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat β-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.

Abbreviations: ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting