title: The first nuclear-encoded complex I mutation in a patient with Leigh syndrome.
abstract: 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.
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Loeffen
authors.forename: J
authors.initials: J
authors.lastname: Smeitink
authors.forename: R
authors.initials: R
authors.lastname: Triepels
authors.forename: R
authors.initials: R
authors.lastname: Smeets
authors.forename: M
authors.initials: M
authors.lastname: Schuelke
authors.forename: R
authors.initials: R
authors.lastname: Sengers
authors.forename: F
authors.initials: F
authors.lastname: Trijbels
authors.forename: B
authors.initials: B
authors.lastname: Hamel
authors.forename: R
authors.initials: R
authors.lastname: Mullaart
authors.forename: L
authors.initials: L
authors.lastname: van den Heuvel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002467:Cell Nucleus / Q000235:genetics*; D002478:Cells, Cultured; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I; D005260:Female; D005288:Ferredoxins / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000097:blood; D015183:Restriction Mapping
chemical_list: D005288:Ferredoxins; D012333:RNA, Messenger; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I