MUTATION OF A NUCLEAR SUCCINATE-DEHYDROGENASE GENE RESULTS IN MITOCHONDRIAL RESPIRATORY-CHAIN DEFICIENCY

We now report a mutation in the nuclear-encoded flavoprotein (Fp) subu nit gene of the succinate dehydrogenase (SDH) in two siblings with com plex II deficiency presenting as Leigh syndrome. Both patients were ho mozygous for an Arg554Trp substitution in the Fp subunit. Their parent s (first cousins) were heterozygous for the mutation that occurred in a conserved domain of the protein and was absent from 120 controls. Th e deleterious effect of the Arg to Trp substitution on the catalytic a ctivity of SDH was observed in a SDH- yeast strain transformed with mu tant Fp cDNA. The Fp subunit gene is duplicated in the human genome (3 q29; 5p15), with only the gene on chromosome 5 expressed in human-hams ter somatic cell hybrids. This is the first report of a nuclear gene m utation causing a mitochondrial respiratory chain deficiency in humans .