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SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome

Abstract

Leigh Syndrome (LS) is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions that is commonly associated with systemic cytochrome c oxidase (COX) deficiency. COX deficiency is an autosomal recessive trait and most patients belong to a single genetic complementation group. DNA sequence analysis of the genes encoding the structural subunits of the COX complex has failed to identify a pathogenic mutation. Using microcell-mediated chromosome transfer, we mapped the gene defect in this disorder to chromosome 9q34 by complementation of the respiratory chain deficiency in patient fibroblasts. Analysis of a candidate gene (SURF1) of unknown function revealed several mutations, all of which predict a truncated protein. These data suggest a role for SURF1 in the biogenesis of the COX complex and define a new class of gene defects causing human neurodegenerative disease.

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Figure 1: COX activity in LS patient fibroblasts after transfer of human chromosome 9 from the K1-9 monochromosomal hybrid cell line.
Figure 2: FISH analysis of deletions in human chromosome 9 in the A9-9del(p) (a) and A9-9HyTK-1.
Figure 3: Ideogram of human chromosome 9 showing the deletion and exclusion maps for the LS COX gene defect.
Figure 4: Analysis of SURF1.
Figure 5: Analysis of SURF1 expression in patient fibroblasts.
Figure 6: Transient expression of SURF1 cDNA restores COX activity.
Figure 7: Comparison of the predicted protein sequences of SURF1 (human, mouse, Fugu) and Shy1 (yeast).

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Acknowledgements

Normal fixed human lymphoblasts were provided by A. Duncan, Montreal Children's Hospital. SURF1 cDNA was a kind gift of M. Fried, Imperial Cancer Research Fund. We thank K.E.M. Hastings for comments on the manuscript. This work was supported in part by research grant 1-FY97-0607 from the March of Dimes Birth Defects Association and by the Medical Research Council of Canada. E.A.S. is an MNI Killam Scholar. C.M. was funded by an MRC fellowship. I.D.B. is funded by an MRC-PMAC fellowship and by Glaxo Wellcome. M.C. is a chercheur-boursier of the FRSQ. J.C.W. is funded in part by a McGill Urology studentship.

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Zhu, Z., Yao, J., Johns, T. et al. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet 20, 337–343 (1998). https://doi.org/10.1038/3804

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