Pathogenic variants in the WDR45 (OMIM: 300,526) gene on chromosome Xp11 are the genetic cause of a rare neurological disorder characterized by increased iron deposition in the basal ganglia. As WDR45 encodes a beta-propeller scaffold protein with a putative role in autophagy, the disease has been named Beta-Propeller Protein-Associated Neurodegeneration (BPAN). BPAN represents one of the four most common forms of Neurodegeneration with Brain Iron Accumulation (NBIA). In the current study, we generated and characterized a whole-body Wdr45 knock-out (KO) mouse model. The model, developed using TALENs, presents a 20-bp deletion in exon 2 of Wdr45. Homozygous females and hemizygous males are viable, proving that systemic depletion of Wdr45 does not impair viability and male fertility in mice. The in-depth phenotypic characterization of the mouse model revealed neuropathology signs at four months of age, neurodegeneration progressing with ageing, hearing and visual impairment, specific haematological alterations, but no brain iron accumulation. Biochemically, Wdr45 KO mice presented with decreased complex I (CI) activity in the brain, suggesting that mitochondrial dysfunction accompanies Wdr45 deficiency. Overall, the systemic Wdr45 KO described here complements the two mouse models previously reported in the literature (PMIDs: 26,000,824, 31,204,559) and represents an additional robust model to investigate the pathophysiology of BPAN and to test therapeutic strategies for the disease.

Xp11 染色体上的WDR45 (OMIM: 300,526) 基因的致病变异是一种罕见神经系统疾病的遗传原因，其特征是基底神经节铁沉积增加。由于WDR45编码一种在自噬中具有推定作用的 β 螺旋桨支架蛋白，因此该疾病被命名为 β 螺旋桨蛋白相关神经变性 (BPAN)。BPAN 代表脑铁累积神经退行性变 (NBIA) 的四种最常见形式之一。在当前的研究中，我们生成并表征了全身Wdr45敲除 (KO) 小鼠模型。该模型是使用 TALEN 开发的，在Wdr45的外显子 2 中存在 20 bp 的缺失。纯合雌性和半合子雄性是可行的，证明系统性耗竭Wdr45不会损害小鼠的活力和雄性生育能力。小鼠模型的深入表型特征揭示了四个月龄时的神经病理学迹象、随年龄增长而进展的神经退行性变、听力和视力障碍、特定的血液学改变，但没有脑铁积累。从生化角度来看，Wdr45 KO小鼠大脑中复合物 I (CI) 活性降低，表明线粒体功能障碍伴随着 Wdr45 缺陷。总体而言，本文描述的系统性 Wdr45 KO 补充了先前文献中报道的两种小鼠模型（PMID：26,000,824、31,204,559），并代表了研究 BPAN 病理生理学和测试该疾病治疗策略的另一个强大模型。