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SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy


We report mutations in SDHAF1, encoding a new LYR-motif protein, in infantile leukoencephalopathy with defective succinate dehydrogenase (SDH, complex II). Disruption of the yeast homolog or expression of variants corresponding to human mutants caused SDH deficiency and failure of OXPHOS-dependent growth, whereas SDH activity and amount were restored in mutant fibroblasts proportionally with re-expression of the wild-type gene. SDHAF1 is the first bona fide SDH assembly factor reported in any organism.

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Figure 1: Protein blot and immunofluorescence studies.
Figure 2: Complementation assays in yeast and human cells.

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This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon-Italy grant number GGP07019, the Italian Ministry of University and Research (FIRB 2003-project RBLA038RMA), The Impulse and Networking Fund of the Helmholtz Alliance for Mental Health in an Ageing Society, HA-215, Deutsche Forschungsgemeinschaft HO 2505/2–1 and MIUR grant 2006069034_003. T.K. and H.P. are members of the German network for mitochondrial disorders (mitoNET, 01GM0862), funded by the German ministry of education and research (BMBF, Bonn, Germany).

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D.G. found SDHAF1 and characterized the mutations in human cells; P.G. and I.F. carried out the experiments in yeast; G.U., R.H., T.K. and H.L. identified the subjects and carried out the clinical workout; P.D., P.G., T.M.S. and H.P. performed linkage analysis on the Italian and Turkish family sets; F.I. carried out the biochemical assays on subjects and the mutational screening on family members, disease and healthy controls; and M.Z. conceived the experimental planning and wrote the manuscript.

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Correspondence to Massimo Zeviani.

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Ghezzi, D., Goffrini, P., Uziel, G. et al. SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 41, 654–656 (2009).

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