MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.
Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.
Pediatric Neurology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Pinchas Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Gali
G
Heimer
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Juha M
JM
Kerätär
Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia.
Lisa G
LG
Riley
Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA 6000, Australia.
Shanti
S
Balasubramaniam
Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Eran
E
Eyal
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Laura P
LP
Pietikäinen
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
J Kalervo
JK
Hiltunen
Metabolic Disease Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Dina
D
Marek-Yagel
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
Jeffrey
J
Hamada
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
Allison
A
Gregory
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
Caleb
C
Rogers
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Penelope
P
Hogarth
Struthers Parkinson's Center, Golden Valley, MN 55427, USA.
Martha A
MA
Nance
Metabolic Disease Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Nechama
N
Shalva
Metabolic Disease Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Alvit
A
Veber
Pediatric Neurology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Michal
M
Tzadok
Pediatric Neurology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Andreea
A
Nissenkorn
Child Neurology Department, Foundation IRCCS, Neurological Institute C. Besta, 20133 Milan, Italy.
Davide
D
Tonduti
Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris, France.
Florence
F
Renaldo
Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia.
Ichraf
I
Kraoua
Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
Celeste
C
Panteghini
Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
Lorella
L
Valletta
Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
Barbara
B
Garavaglia
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of NSW, Sydney, NSW 2010, Australia.
Mark J
MJ
Cowley
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
Velimir
V
Gayevskiy
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; St Vincent's Clinical School, University of NSW, Sydney, NSW 2010, Australia.
Tony
T
Roscioli
Neurology Department, Princess Margaret Hospital, Perth, WA 6000, Australia.
Jonathon M
JM
Silberstein
Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Chen
C
Hoffmann
The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
Annick
A
Raas-Rothschild
Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
Valeria
V
Tiranti
Metabolic Disease Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Yair
Y
Anikster
Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics & Child Health, Sydney Medical School, University of Sydney, Sydney, NSW 2145, Australia; Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Murdoch Children's Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
John
J
Christodoulou
Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Alexander J
AJ
Kastaniotis
Pediatric Neurology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel; The Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel. Electronic address: bruria.benzeev@sheba.health.gov.il.
Bruria
B
Ben-Zeev
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA; Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: hayflick@ohsu.edu.
Susan J
SJ
Hayflick
D001479:Basal Ganglia / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D020821:Dystonic Disorders / Q000235:genetics*; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D005347:Fibroblasts; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D009896:Optic Atrophy / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
D005227:Fatty Acids; D022821:RNA Splice Sites; D044925:Oxidoreductases Acting on CH-CH Group Donors; C434934:trans-2-enoyl-CoA reductase (NADPH)