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

Wortmann, S.B.; Vaz, F.M.; Gardeitchik, T.; Vissers, L.E.L.M.; Renkema, G.H.; Schuurs-Hoeijmakers, J.H.M.; Kulik, W.; Lammens, M.; Christin, C.; Kluijtmans, L.A.J.; Rodenburg, R.J.; Nijtmans, L.G.J.; Grünewald, A.; Klein, C.; Gerhold, J.M.; Kozicz, T.; van Hasselt, P.M.; Harakalova, M.; Kloosterman, W.; Barić, I. ... de Brouwer, A.P.M. (2012). Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nature Genetics, 44 (7), 797−802.10.1038/ng.2325.
ajakirjaartikkel
Wortmann, S.B.; Vaz, F.M.; Gardeitchik, T.; Vissers, L.E.L.M.; Renkema, G.H.; Schuurs-Hoeijmakers, J.H.M.; Kulik, W.; Lammens, M.; Christin, C.; Kluijtmans, L.A.J.; Rodenburg, R.J.; Nijtmans, L.G.J.; Grünewald, A.; Klein, C.; Gerhold, J.M.; Kozicz, T.; van Hasselt, P.M.; Harakalova, M.; Kloosterman, W.; Barić, I. ... de Brouwer, A.P.M.
  • Inglise
Nature Genetics
1061-4036
44
7
2012
797802
Ilmunud
1.1. Teadusartiklid, mis on kajastatud Web of Science andmebaasides Science Citation Index Expanded, Social Sciences Citation Index, Arts & Humanities Citation Index ja/või andmebaasis Scopus (v.a. kogumikud)
WOS

Viited terviktekstile

dx.doi.org/10.1038/ng.2325

Lisainfo

Article. 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.