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The 14484 ND6 mtDNA mutation in Leber hereditary optic neuropathy does not affect fibroblast complex I activity.

To the Editor: Despite clear associations of mtDNA mutations with Leber hereditary optic neuropathy (LHON), the precise molecular basis of the disease remains to be characterized. In particular, reported defects of respiratory-chain function are not consistent for the different primary mutations. A severe defect in rotenone-sensitive NADH: ubiquinone oxidoreductase (complex I) activity has been reported with the 3460 ND1 mutation in lymphocytes, platelets, and fibroblasts (Majander et al. 1991; Smith et al. 1994; Cock et al. 1995), but there are conflicting data for the 11778 ND4 mutation. Normal complex I function has been demonstrated in muscle (Larsson et al. 1991) and lymphocytes (Majander et al. 1991), and a mild defect in platelets (Smith et al. 1994) has been reported. Recently, it has been proposed that the 11778 mutation causes a more subtle reduction in rotenone sensitivity and substrate binding to complex I (Esposti et al. 1994), although complex I activity was found to be normal by using standard spectrophotometric assays. Thus, despite the presence of 100% mutant mtDNA in the cells analyzed, a consistent respiratory-chain defect has been identified only for the 3460 primary LHON mutation. Little biochemical data are available for the primary LHON mutation at position 14484 (ND6). This mutation accounts for 10%-15% of all LHON cases (Riordan-Eva and Harding 1995), and it is generally considered to be less deleterious with a better visual outcome (Brown et al. 1994). Analysis of respiratory-chain function in 14484 patients has thus far been limited to the Queensland family first described by Wallace (1970). While exhibiting a severe complex I defect in platelet mitochondria (Parker et al. 1989), this family also harbored a mutation at position 4160 (ND1) (Howell et al. 1991) and is clinically very atypical for LHON because of the presence of a severe CNS involvement including a childhood encephalopathy. We have studied respiratory-chain function in a family with the 14484 mutation that is not known to carry any other LHON mutations. Restriction-enzyme analysis of PCR-amplified mtDNA confirmed the presence of the homoplasmic 14484 G-to-A mutation in fibroblast cultures established from the affected male proband (EC, age 45 years), his unaffected mother (HC, age 75 years), and his unaffected sister (MM, age 39 years). The 3460, 11778, and 4160 mutations were not detected. Mitochondrial respiratory-chain function was assessed by standard spectrophotometric techniques (Smith et al. 1994) on mitochondrial fractions prepared from cultured fibroblasts and was compared to those of seven healthy controls (ages 31-77 years). The results showed normal activities of rotenone-sensitive NADH: ubiquinone reductase (complex I), succinate cytochrome c reductase (complex II/III), and cytochrome oxidase (complex IV) in all the 14484 patients. This was true, expressed either as specific activities or as a citrate synthase ratio (table 1). There was no complex I defect such as that described in the 14484/4160 Queensland family. It was originally suggested that the CNS manifestations in this family are caused by the 4160 mutation rather than the 14484 LHON mutation (Howell et al. 1991). Our data suggest that the biochemical abnormality shown by Parker et al. in 1989 is also likely to be due to the 4160 mutation. In contrast to the 11778 and 3460 mutations, which alter highly conserved amino acids, the 14484 mutation converts only a moderately conserved methionine to valine (Mackey and Howell 1992). However, this amino acid change has not been