A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease

Mol Genet Metab. 2009 Apr;96(4):189-95. doi: 10.1016/j.ymgme.2008.12.004. Epub 2009 Jan 29.


Mitochondrial diseases have been shown to result from mutations in mitochondrial genes located in either the nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Mitochondrial OXPHOS complex I has 45 subunits encoded by 38 nuclear and 7 mitochondrial genes. Two male patients in a putative X-linked pedigree exhibiting a progressive neurodegenerative disorder and a severe muscle complex I enzyme defect were analyzed for mutations in the 38 nDNA and seven mtDNA encoded complex I subunits. The nDNA X-linked NDUFA1 gene (MWFE polypeptide) was discovered to harbor a novel missense mutation which changed a highly conserved glycine at position 32 to an arginine, shown to segregate with the disease. When this mutation was introduced into a NDUFA1 null hamster cell line, a substantial decrease in the complex I assembly and activity was observed. When the mtDNA of the patient was analyzed, potentially relevant missense mutations were observed in the complex I genes. Transmitochondrial cybrids containing the patient's mtDNA resulted in a mild complex I deficiency. Interestingly enough, the nDNA encoded MWFE polypeptide has been shown to interact with various mtDNA encoded complex I subunits. Therefore, we hypothesize that the novel G32R mutation in NDUFA1 is causing complex I deficiency either by itself or in synergy with additional mtDNA variants.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CHO Cells
  • Child
  • Child, Preschool
  • Cricetinae
  • Cricetulus
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics
  • Disease Progression
  • Electron Transport Complex I / genetics*
  • Female
  • Humans
  • Male
  • Mitochondria, Muscle / metabolism
  • Mitochondrial Diseases / complications*
  • Mitochondrial Diseases / genetics*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation / genetics*
  • NADH Dehydrogenase / chemistry
  • NADH Dehydrogenase / genetics*
  • Neurodegenerative Diseases / complications*
  • Neurodegenerative Diseases / genetics*
  • Pedigree
  • Protein Subunits / genetics


  • DNA, Mitochondrial
  • Protein Subunits
  • NADH Dehydrogenase
  • Electron Transport Complex I
  • NDUFA1 protein, human