Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement.

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Protasoni, Margherita 
Bruno, Claudio 
Donati, Maria Alice 
Mohamoud, Khadra 
Severino, Mariasavina 

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.

Brain MRI, Complex I assembly, Complex I assembly factors, Human complex I, Mitochondrial disorders, NUBPL, Adolescent, Adult, Brain, Child, DNA, Mitochondrial, Female, Genetic Variation, Heterozygote, Humans, Infant, Infant, Newborn, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Mitochondria, Mitochondrial Proteins, Mutation, Young Adult
Journal Title
Mol Genet Metab
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Elsevier BV
Medical Research Council (MC_UP_1002/1)
MRC (MC_UP_1002/1)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (705560)
Medical Research Council (MC_UU_00015/8)
European Research Council (322424)
MRC (MC_UU_00015/8)
Medical Research Council (MC_U105674181)