Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation

Hum Mutat. 2021 Jun;42(6):699-710. doi: 10.1002/humu.24195. Epub 2021 Mar 25.


Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature among mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and more than 80 monogenic causes have been involved in the disease. In this report, we describe seven patients from four unrelated families harboring novel NDUFA12 variants, with six of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next-generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis, and western blot analysis. All patients displayed novel homozygous mutations in the NDUFA12 gene, leading to the virtual absence of the corresponding protein. Surprisingly, despite the fact that in none of the analyzed patients, NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.

Keywords: Leigh syndrome; NADH ubiquinone oxidoreductase; NDUFA12; mitochondrial disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Cohort Studies
  • Consanguinity
  • Electron Transport Complex I / genetics
  • Family
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Italy
  • Leigh Disease / complications
  • Leigh Disease / genetics*
  • Leigh Disease / pathology
  • Male
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology
  • NADPH Dehydrogenase / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide


  • NDUFA12 protein, human
  • NADPH Dehydrogenase
  • Electron Transport Complex I