2. Academic Validation
  3. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness

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

  • Nat Genet. 2012 Jun 10;44(7):797-802. doi: 10.1038/ng.2325.
Saskia B Wortmann 1,  Frédéric M Vaz,  Thatjana Gardeitchik,  Lisenka E L M Vissers,  G Herma Renkema,  Janneke H M Schuurs-Hoeijmakers,  Wim Kulik,  Martin Lammens,  Christin Christin,  Leo A J Kluijtmans,  Richard J Rodenburg,  Leo G J Nijtmans,  Anne Grünewald,  Christine Klein,  Joachim M Gerhold,  Tamas Kozicz,  Peter M van Hasselt,  Magdalena Harakalova,  Wigard Kloosterman,  Ivo Barić,  Ewa Pronicka,  Sema Kalkan Ucar,  Karin Naess,  Kapil K Singhal,  Zita Krumina,  Christian Gilissen,  Hans van Bokhoven,  Joris A Veltman,  Jan A M Smeitink,  Dirk J Lefeber,  Johannes N Spelbrink,  Ron A Wevers,  Eva Morava,  Arjan P M de Brouwer
Affiliations

Affiliation

  • 1 Department of Pediatrics, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands. s.wortmann@cukz.umcn.nl
PMID: 22683713 DOI: 10.1038/ng.2325
Abstract

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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