Background The nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).
Methods Whole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.
Results The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.
Conclusion We report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.
- clinical genetics
- metabolic disorders
- molecular genetics
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Contributors VK and PSE established the study and recruited patients. VK, SP, DAS and MKK provided patient/family samples and clinical information. LW, KH, ST, MS and EC performed and analysed the genetic experiments. AEM, AES, PHS, BB, BRC, SW, RK and JB performed and/or analysed the functional and/or biochemical experiments. ANH provided analyses of MRIs. VK, RAD, KH, MS, EC, EH and PSE analysed and interpreted clinical and/or genetic data. VK, RAD and PSE wrote the manuscript. CC, JB and EH provided critical revisions.
Funding Funding for these studies were provided by the Spooner Girls Foundation, CART (Center for Autism Research and Translation) and the ICTS (Institute of Clinical Translational Science, UC Irvine).
Competing interests EH and PSE are employees of Population Bio. BRC, SW, RK, ST and EC are employees of Ambry Genetics.
Patient consent for publication Not required.
Ethics approval Ethics approval for this study was obtained from the University of California, Irvine.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.
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