X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy

Ann Neurol. 2007 Jan;61(1):73-83. doi: 10.1002/ana.21036.


Objective: Mitochondrial complex I deficiency is the commonest diagnosed respiratory chain defect, being genetically heterogeneous. The male preponderance of previous patient cohorts suggested an X-linked underlying genetic defect. We investigated mutations in the X-chromosomal complex I structural genes, NDUFA1 and NDUFB11, as a novel cause of mitochondrial encephalomyopathy.

Methods: We sequenced 12 nuclear genes and the mitochondrial DNA-encoded complex I genes in 26 patients with respiratory chain complex I defect. Novel mutations were confirmed by polymerase chain reaction restriction length polymorphism. Assembly/stability studies in fibroblasts were performed using two-dimensional blue native gel electrophoresis.

Results: Two novel p.Gly8Arg and p.Arg37Ser hemizygous mutations in NDUFA1 were identified in two unrelated male patients presenting with Leigh's syndrome and with myoclonic epilepsy and developmental delay, respectively. Two-dimensional blue native gel electrophoresis showed decreased levels of intact complex I with no accumulation of lower molecular weight subcomplexes, indicating that assembly, stability, or both are compromised.

Interpretation: Mutations in the X-linked NDUFA1 gene result in complex I defect and encephalomyopathy. Assembly/stability analysis might give an explanation for the different clinical phenotypes and become useful for future diagnostic purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine / genetics
  • DNA Mutational Analysis / methods
  • Electron Transport Complex I / metabolism
  • Electrophoresis, Gel, Two-Dimensional / methods
  • Female
  • Genes, X-Linked*
  • Glycine / genetics
  • Humans
  • Male
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Encephalomyopathies / pathology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • NADH Dehydrogenase / genetics*
  • Sequence Alignment
  • Serine / genetics


  • Serine
  • Arginine
  • NADH Dehydrogenase
  • Electron Transport Complex I
  • NDUFA1 protein, human
  • Glycine