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

  • Author(s): Potluri, Prasanth
  • Davila, Antonio
  • Ruiz-Pesini, Eduardo
  • Mishmar, Dan
  • O'Hearn, Sean
  • Hancock, Saege
  • Simon, Mariella
  • Scheffler, Immo E
  • Wallace, Douglas C
  • Procaccio, Vincent
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693342/
No data is associated with this publication.
Abstract

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.

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