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
  • 1. Department of Pediatrics, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands. [email protected]
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.