Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency

Am J Hum Genet. 2001 Jun;68(6):1344-52. doi: 10.1086/320603. Epub 2001 May 7.


Reduced nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest complex of the mitochondrial respiratory chain and complex I deficiency accounts for approximately 30% cases of respiratory-chain deficiency in humans. Only seven mitochondrial DNA genes, but >35 nuclear genes encode complex I subunits. In an attempt to elucidate the molecular bases of complex I deficiency, we studied the six most-conserved complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) in a series of 36 patients with isolated complex I deficiency by denaturing high-performance liquid chromatography and by direct sequencing of the corresponding cDNA from cultured skin fibroblasts. In 3/36 patients, we identified, for the first time, five point mutations (del222, D252G, M707V, R241W, and R557X) and one large-scale deletion in the NDUFS1 gene. In addition, we found six novel NDUFV1 mutations (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989-990) in three other patients. The six unrelated patients presented with hypotonia, ataxia, psychomotor retardation, or Leigh syndrome. These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / enzymology
  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Amino Acid Sequence
  • Base Sequence
  • Catalytic Domain
  • Cell Nucleus / genetics
  • Child, Preschool
  • Chromatography, High Pressure Liquid
  • DNA Mutational Analysis
  • Electron Transport / genetics
  • Electron Transport Complex I
  • Exons / genetics
  • Female
  • Fibroblasts
  • Genetic Counseling
  • Haplotypes / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Leigh Disease / enzymology
  • Leigh Disease / genetics
  • Leigh Disease / pathology
  • Mitochondria, Muscle / enzymology*
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / pathology
  • Molecular Sequence Data
  • NADH Dehydrogenase
  • NADH, NADPH Oxidoreductases / chemistry
  • NADH, NADPH Oxidoreductases / deficiency*
  • NADH, NADPH Oxidoreductases / genetics*
  • Nucleic Acid Denaturation
  • Point Mutation / genetics*
  • Proteins / chemistry
  • Proteins / genetics*
  • Sequence Alignment
  • Sequence Deletion / genetics*


  • NDUFV1 protein, human
  • Proteins
  • NADH, NADPH Oxidoreductases
  • NADH Dehydrogenase
  • Electron Transport Complex I

Associated data

  • GENBANK/AC005329
  • GENBANK/AC007383
  • GENBANK/AF053069
  • GENBANK/AF053070
  • GENBANK/U65579
  • OMIM/157655
  • OMIM/161015
  • OMIM/601825
  • OMIM/602141
  • OMIM/603322
  • OMIM/603359
  • RefSeq/NM_002493
  • RefSeq/NM_014222