Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.
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.
Department of Pediatrics, Radboud University Nijmegen Medical Centre (RUNMC), Nijmegen, The Netherlands. s.wortmann@cukz.umcn.nl
Saskia B
SB
Wortmann
Frédéric M
FM
Vaz
Thatjana
T
Gardeitchik
Lisenka E L M
LE
Vissers
G Herma
GH
Renkema
Janneke H M
JH
Schuurs-Hoeijmakers
Wim
W
Kulik
Martin
M
Lammens
Christin
C
Christin
Leo A J
LA
Kluijtmans
Richard J
RJ
Rodenburg
Leo G J
LG
Nijtmans
Anne
A
Grünewald
Christine
C
Klein
Joachim M
JM
Gerhold
Tamas
T
Kozicz
Peter M
PM
van Hasselt
Magdalena
M
Harakalova
Wigard
W
Kloosterman
Ivo
I
Barić
Ewa
E
Pronicka
Sema Kalkan
SK
Ucar
Karin
K
Naess
Kapil K
KK
Singhal
Zita
Z
Krumina
Christian
C
Gilissen
Hans
H
van Bokhoven
Joris A
JA
Veltman
Jan A M
JA
Smeitink
Dirk J
DJ
Lefeber
Johannes N
JN
Spelbrink
Ron A
RA
Wevers
Eva
E
Morava
Arjan P M
AP
de Brouwer
D000595:Amino Acid Sequence; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D002308:Cardiolipins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D003638:Deafness / Q000235:genetics* / Q000378:metabolism; D004421:Dystonia / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010085:Oxidative Phosphorylation; D010715:Phosphatidylglycerols / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
D002308:Cardiolipins; D010715:Phosphatidylglycerols; D010743:Phospholipids; D002784:Cholesterol; D002265:Carboxylic Ester Hydrolases; C576043:SERAC1 protein, human