Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.
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Publication year
2012Author(s)
Source
Nature Genetics, 44, 7, (2012), pp. 797-802ISSN
Annotation
01 juli 2012
Publication type
Article / Letter to editor
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Organization
Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
Human Genetics
Pathology
Anatomy
Neurology
Journal title
Nature Genetics
Volume
vol. 44
Issue
iss. 7
Page start
p. 797
Page end
p. 802
Subject
DCN MP - Plasticity and memory IGMD 9: Renal disorder; DCN NN - Brain networks and neuronal communication; DCN PAC - Perception action and control IGMD 4: Glycostation disorders; IGMD 4: Glycostation disorders; IGMD 8: Mitochondrial medicine; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; IGMD 8: Mitochondrial medicine NCMLS 5: Membrane transport and intracellular motility; NCMLS 6: Genetics and epigenetic pathways of disease DCN MP - Plasticity and memory; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disordersAbstract
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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- Faculty of Medical Sciences [90359]
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