NUBPL (Nucleotide-binding protein like) protein encodes a member of the Mrp/NBP35 ATP-binding proteins family, deemed to be involved in mammalian complex I (CI) assembly process. Exome sequencing of a patient presenting with infantile-onset hepatopathy, renal tubular acidosis, developmental delay, short stature, leukoencephalopathy with minimal cerebellar involvement and multiple OXPHOS deficiencies revealed the presence of two novel pathogenic compound heterozygous variants in NUBPL (p.Phe242Leu/p.Leu104Pro). We investigated patient's and control immortalised fibroblasts and demonstrated that both the peripheral and the membrane arms of complex I are undetectable in mutant NUBPL cells, resulting in virtually absent CI holocomplex and loss of enzyme activity. In addition, complex III stability was moderately affected as well. Lentiviral-mediated expression of the wild-type NUBPL cDNA rescued both CI and CIII assembly defects, confirming the pathogenicity of the variants. In conclusion, this is the first report describing a complex multisystemic disorder due to NUBPL defect. In addition, we confirmed the role of NUBPL in Complex I assembly associated with secondary effect on Complex III stability and we demonstrated a defect of mtDNA-related translation which suggests a potential additional role of NUBPL in mtDNA expression.

中文翻译：

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核苷酸结合蛋白样蛋白（NUBPL）中的新型复合杂合病原体变异体引起多系统性参与的白质脑病。

NUBPL（类似核苷酸的结合蛋白）蛋白编码Mrp / NBP35 ATP结合蛋白家族的成员，被认为与哺乳动物复合物I（CI）组装过程有关。一名患儿出现小儿肝病，肾小管酸中毒，发育迟缓，身材矮小，小脑白细胞病变，小脑受累最小和OXPHOS缺乏症的患者的外显子测序显示NUBPL中存在两种新的致病性化合物杂合子变体（p.Phe242Leu / p。 Leu104Pro）。我们调查了患者和对照永生的成纤维细胞，并证明在突变的NUBPL细胞中无法检测到复合物I的外围和膜臂，从而导致CI完整复合物的缺失和酶活性的丧失。另外，复合物III的稳定性也受到中等程度的影响。慢病毒介导的野生型NUBPL cDNA的表达挽救了CI和CIII装配缺陷，证实了这些变体的致病性。总之，这是第一个描述由于NUBPL缺陷而引起的复杂的多系统疾病的报告。此外，我们证实了NUBPL在复合物I装配中的作用与对复合物III稳定性的次级影响有关，并且我们证明了mtDNA相关翻译的缺陷，这表明NUBPL在mtDNA表达中可能具有其他作用。