Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness

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Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking.

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Figure 1: Key phospholipids and a schematic representation of SERAC1.
Figure 2: SERAC1 and its role in phosphatidylglycerol remodeling and cholesterol trafficking.
Figure 3: Cardiolipin species composition in patients and controls.
Figure 4: Subcellular localization of SERAC1.
Figure 5: The ratio of phosphatidylglycerol (PG)-34:1 to phosphatidylglycerol-36:1 in patient fibroblasts complemented with wild-type SERAC1.

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We thank the patients and their parents for participating in this study. The study was financially supported by the Dutch Brain Foundation (2010(1)-30 to A.P.M.d.B. and 2011(1)-101 to E.M.), the EU 7th framework programme (grant 241995 (GENCODYS) to H.v.B.), the Netherlands Organisation for Health Research and Development (ZonMW 916.86.016 to L.E.L.M.V. and ZonMW 917.66.363 to J.A.V.) and the Ministry of Science, Education and Sports of the Republic of Croatia (108-1081870-1885 to I.B.). S.B.W. is supported by the 'Stichting Energy4all'. T.G. is a recipient of the 'IGMD junior scientist grant 2010'. J.M.G. is a recipient of an EMBO long-term fellowship cofunded by Marie Curie Actions EMBO long-term fellowship 1066_2011 (including MCA-EMBOCOFUND2010 and GA-2010-267146). J.N.S. is supported by the Academy of Finland (Centre of Excellence funding), the Tampere University Hospital Medical Research Fund (9J119, 9K126 and 9L097) and the Netherlands Organization for Scientific Research (NWO: VICI grant 865.10.004). We are grateful to B. van den Ende, M. Seders and S. van de Velde-Vissers (Department of Human Genetics, RUNMC, Nijmegen), as well as to K. Janssen and A. van Heck-Kappen (Department of Laboratory Medicine, RUNMC, Nijmegen), A. Leenders (Department of Pediatrics, RUNMC, Nijmegen), the colleagues of the tissue culture lab of the LGEM (Department of Laboratory Medicine, RUNMC, Nijmegen) and F.S. Stet (University of Amsterdam) for excellent technical assistance. For technical assistance, data analysis, critical discussion and exome sequencing, we are grateful to the Genomic Disorders groups of the Department of Human Genetics, RUNMC, Nijmegen (headed by H. Brunner) and the Department of Medical Genetics, University Medical Center, Utrecht (headed by E. Cuppen). We also thank F.A.J. Muskiet, F. Preijers, A. van Kampen and J. van Dam for useful discussions.

Author information

S.B.W., E.M., R.A.W. and A.P.M.d.B. designed and supervised the study. S.B.W. and E.M. characterized MEGDEL syndrome and collected clinical data and patient tissues. L.A.J.K. performed and supervised the metabolic metabolite screening. P.M.v.H., I.B., E.P., S.K.U., K.N., K.K.S., Z.K. and J.A.M.S. diagnosed and referred patients. L.E.L.M.V., C.G., J.H.M.S.-H., J.A.V., M.H., W. Kloosterman, H.v.B. and A.P.M.d.B. performed the genetic studies and identified the causative genetic defect. G.H.R., R.J.R., T.G. and A.P.M.d.B. performed the lentiviral complementation. F.M.V., C.C. and W. Kulik performed the phospholipid spectra analysis and interpreted the data together with S.B.W., E.M., R.A.W. and A.P.M.d.B. D.J.L. performed and interpreted the filipin staining. A.G. and C.K. performed and interpreted the studies on autophagy and mitophagy. T.G., L.G.J.N., T.K., J.M.G. and J.N.S. performed colocalization and western blotting studies on SERAC1. T.K. performed the studies on fusion-fission. R.J.R. performed and interpreted oxidative phosphorylation measurements. M.L. captured and interpreted electron microscopic pictures of muscle tissue. F.M.V. and E.M. contributed to the draft manuscript. S.B.W., R.A.W. and A.P.M.d.B. prepared the final manuscript.

Correspondence to Saskia B Wortmann or Ron A Wevers.

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