Reference : Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function an...
Scientific journals : Article
Scientific journals : Article
http://hdl.handle.net/10993/24251
Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.
English
Wortmann, Saskia B. [> >]
Vaz, Frederic M. [> >]
Gardeitchik, Thatjana [> >]
Vissers, Lisenka E. L. M. [> >]
Renkema, G. Herma [> >]
Schuurs-Hoeijmakers, Janneke H. M. [> >]
Kulik, Wim [> >]
Lammens, Martin [> >]
Christin, Christin [> >]
Kluijtmans, Leo A. J. [> >]
Rodenburg, Richard J. [> >]
Nijtmans, Leo G. J. [> >]
Grünewald, Anne [> >]
Klein, Christine [> >]
Gerhold, Joachim M. [> >]
Kozicz, Tamas [> >]
van Hasselt, Peter M. [> >]
Harakalova, Magdalena [> >]
Kloosterman, Wigard [> >]
Baric, Ivo [> >]
Pronicka, Ewa [> >]
Ucar, Sema Kalkan [> >]
Naess, Karin [> >]
Singhal, Kapil K. [> >]
Krumina, Zita [> >]
Gilissen, Christian [> >]
van Bokhoven, Hans [> >]
Veltman, Joris A. [> >]
Smeitink, Jan A. M. [> >]
Lefeber, Dirk J. [> >]
Spelbrink, Johannes N. [> >]
Wevers, Ron A. [> >]
Morava, Eva [> >]
de Brouwer, Arjan P. M. [> >]
2012
Nature genetics
44
7
797-802
Yes (verified by ORBilu)
International
1061-4036
1546-1718
United States
[en] Amino Acid Sequence ; Carboxylic Ester Hydrolases/genetics/metabolism ; Cardiolipins/genetics/metabolism ; Cell Line, Transformed ; Cell Line, Tumor ; Cholesterol/genetics/metabolism ; Deafness/genetics/metabolism ; Dystonia/genetics/metabolism ; Exome ; Fibroblasts/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Mitochondria/genetics/metabolism ; Molecular Sequence Data ; Mutation ; Oxidative Phosphorylation ; Phosphatidylglycerols/genetics/metabolism ; Phospholipids/genetics/metabolism ; Sequence Alignment
[en] 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.
Researchers ; Students
http://hdl.handle.net/10993/24251

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