TY - JOUR
T1 - Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness
AU - Wortmann, Saskia B.
AU - Vaz, Frédéric M.
AU - Gardeitchik, Thatjana
AU - Vissers, Lisenka E.L.M.
AU - Renkema, G. Herma
AU - Schuurs-Hoeijmakers, Janneke H.M.
AU - Kulik, Wim
AU - Lammens, Martin
AU - Christin, Christin
AU - Kluijtmans, Leo A.J.
AU - Rodenburg, Richard J.
AU - Nijtmans, Leo G.J.
AU - Grünewald, Anne
AU - Klein, Christine
AU - Gerhold, Joachim M.
AU - Kozicz, Tamas
AU - Van Hasselt, Peter M.
AU - Harakalova, Magdalena
AU - Kloosterman, Wigard
AU - Barić, Ivo
AU - Pronicka, Ewa
AU - Ucar, Sema Kalkan
AU - Naess, Karin
AU - Singhal, Kapil K.
AU - Krumina, Zita
AU - Gilissen, Christian
AU - Van Bokhoven, Hans
AU - Veltman, Joris A.
AU - Smeitink, Jan A.M.
AU - Lefeber, Dirk J.
AU - Spelbrink, Johannes N.
AU - Wevers, Ron A.
AU - Morava, Eva
AU - De Brouwer, Arjan P.M.
N1 - Funding Information:
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 (10810818701885 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 longterm fellowship cofunded by Marie Curie Actions EMBO longterm fellowship 1066_2011 (including MCAEMBOCOFUND2010 and GA2010-267146). 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 VeldeVissers (Department of Human Genetics, RUNMC, Nijmegen), as well as to K. Janssen and A. van HeckKappen (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.
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862979366&partnerID=8YFLogxK
U2 - 10.1038/ng.2325
DO - 10.1038/ng.2325
M3 - Article
C2 - 22683713
AN - SCOPUS:84862979366
SN - 1061-4036
VL - 44
SP - 797
EP - 802
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -