The first nuclear-encoded complex I mutation in a patient with Leigh syndrome

Am J Hum Genet. 1998 Dec;63(6):1598-608. doi: 10.1086/302154.


Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest multiprotein enzyme complex of the respiratory chain. The nuclear-encoded NDUFS8 (TYKY) subunit of complex I is highly conserved among eukaryotes and prokaryotes and contains two 4Fe4S ferredoxin consensus patterns, which have long been thought to provide the binding site for the iron-sulfur cluster N-2. The NDUFS8 cDNA contains an open reading frame of 633 bp, coding for 210 amino acids. Cycle sequencing of amplified NDUFS8 cDNA of 20 patients with isolated enzymatic complex I deficiency revealed two compound heterozygous transitions in a patient with neuropathologically proven Leigh syndrome. The first mutation was a C236T (P79L), and the second mutation was a G305A (R102H). Both mutations were absent in 70 control alleles and cosegregated within the family. A progressive clinical phenotype proceeding to death in the first months of life was expressed in the patient. In the 19 other patients with enzymatic complex I deficiency, no mutations were found in the NDUFS8 cDNA. This article describes the first molecular genetic link between a nuclear-encoded subunit of complex I and Leigh syndrome.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Nucleus / genetics*
  • Cells, Cultured
  • Consensus Sequence
  • DNA Mutational Analysis
  • Electron Transport Complex I
  • Female
  • Ferredoxins / genetics
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Gene Expression
  • Heterozygote
  • Humans
  • Infant, Newborn
  • Leigh Disease / enzymology
  • Leigh Disease / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation*
  • NADH, NADPH Oxidoreductases / deficiency
  • NADH, NADPH Oxidoreductases / genetics*
  • NADH, NADPH Oxidoreductases / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / blood
  • Restriction Mapping


  • Ferredoxins
  • RNA, Messenger
  • NADH, NADPH Oxidoreductases
  • Electron Transport Complex I

Associated data

  • GENBANK/U65579