Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness
- 10 June 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 44 (7), 797-802
- https://doi.org/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.Keywords
This publication has 24 references indexed in Scilit:
- Nonesterified cholesterol content of lysosomes modulates susceptibility to oxidant-induced permeabilizationFree Radical Biology & Medicine, 2011
- The 3‐methylglutaconic acidurias: what's new?Journal of Inherited Metabolic Disease, 2010
- Exome Sequencing Identifies WDR35 Variants Involved in Sensenbrenner SyndromeAmerican Journal of Human Genetics, 2010
- A method and server for predicting damaging missense mutationsNature Methods, 2010
- Cardiolipin acts as a mitochondrial signalling platform to launch apoptosisBiochimica et Biophysica Acta (BBA) - Biomembranes, 2009
- The role of cardiolipin in the structural organization of mitochondrial membranesBiochimica et Biophysica Acta (BBA) - Biomembranes, 2009
- Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca2+ Signaling and Cell SurvivalCell, 2007
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- A novel X-linked gene, G4.5. is responsible for Barth syndromeNature Genetics, 1996
- News from the interface: the molecular structures of triacyglyceride lipasesTrends in Biochemical Sciences, 1993