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Original research
NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum
  1. Virginia Kimonis1,
  2. Rehab al Dubaisi1,
  3. Andrew E Maclean2,3,
  4. Kathy Hall1,
  5. Lan Weiss1,
  6. Alexander E Stover4,
  7. Philip H Schwartz4,
  8. Bethany Berg1,
  9. Cheng Cheng1,
  10. Sumit Parikh5,
  11. Blair R Conner6,
  12. Sitao Wu6,
  13. Anton N Hasso7,
  14. Daryl A Scott8,9,
  15. Mary Kay Koenig10,
  16. Rachid Karam6,
  17. Sha Tang6,
  18. Moyra Smith1,
  19. Elizabeth Chao1,6,
  20. Janneke Balk2,
  21. Eli Hatchwell11,
  22. Peggy S Eis12
  1. 1Division of Genetics and Metabolism, Department of Pediatrics, University of California Irvine, Irvine, California, USA
  2. 2Department of Biological Chemistry, John Innes Centre, Norwich, Norfolk, UK
  3. 3Wellcome Centre for Integrative Parasitology, University of Glasgow, Glasgow, Glasgow, UK
  4. 4CHOC National Human Neural Stem Cell Resource, Children's Hospital of Orange County Research Institute, Orange, California, USA
  5. 5Center for Pediatric Neurology, Cleveland Clinic, Cleveland, Ohio, USA
  6. 6Ambry Genetics Corp, Aliso Viejo, California, USA
  7. 7Radiological Sciences, University of California Irvine School of Medicine, Irvine, California, USA
  8. 8Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  9. 9Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA
  10. 10Department of Pediatrics, University of Texas McGovern Medical School, Houston, Texas, USA
  11. 11Population Bio UK, Inc, Begbroke, Oxfordshire, UK
  12. 12Population Bio, Inc, New York, New York, USA
  1. Correspondence to Dr Virginia Kimonis, Division of Genetics and Metabolism, Department of Pediatrics, University of California Irvine, Irvine, CA 92868, USA; vkimonis{at}; Dr Peggy S Eis, Population Bio, Inc, New York, NY, USA; pegeis{at}


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
  • neurology
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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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