MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Gali Heimer; Juha M Kerätär; Lisa G Riley; Shanti Balasubramaniam; Eran Eyal; Laura P Pietikäinen; J Kalervo Hiltunen; Dina Marek-Yagel; Jeffrey Hamada; Allison Gregory; Caleb Rogers; Penelope Hogarth; Martha A Nance; Nechama Shalva; Alvit Veber; Michal Tzadok; Andreea Nissenkorn; Davide Tonduti; Florence Renaldo; University of Washington Center for Mendelian Genomics; Ichraf Kraoua; Celeste Panteghini; Lorella Valletta; Barbara Garavaglia; Mark J Cowley; Velimir Gayevskiy; Tony Roscioli; Jonathon M Silberstein; Chen Hoffmann; Annick Raas-Rothschild; Valeria Tiranti; Yair Anikster; John Christodoulou; Alexander J Kastaniotis; Bruria Ben-Zeev; Susan J Hayflick

doi:10.1016/j.ajhg.2016.09.021

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder

Am J Hum Genet. 2016 Dec 1;99(6):1229-1244. doi: 10.1016/j.ajhg.2016.09.021. Epub 2016 Nov 3.

Authors

Gali Heimer¹, Juha M Kerätär², Lisa G Riley³, Shanti Balasubramaniam⁴, Eran Eyal⁵, Laura P Pietikäinen², J Kalervo Hiltunen², Dina Marek-Yagel⁶, Jeffrey Hamada⁷, Allison Gregory⁷, Caleb Rogers⁷, Penelope Hogarth⁸, Martha A Nance⁹, Nechama Shalva⁶, Alvit Veber⁶, Michal Tzadok¹⁰, Andreea Nissenkorn¹¹, Davide Tonduti¹², Florence Renaldo¹³; University of Washington Center for Mendelian Genomics; Ichraf Kraoua¹⁴, Celeste Panteghini¹⁵, Lorella Valletta¹⁵, Barbara Garavaglia¹⁵, Mark J Cowley¹⁶, Velimir Gayevskiy¹⁷, Tony Roscioli¹⁶, Jonathon M Silberstein¹⁸, Chen Hoffmann¹⁹, Annick Raas-Rothschild²⁰, Valeria Tiranti¹⁵, Yair Anikster²¹, John Christodoulou²², Alexander J Kastaniotis², Bruria Ben-Zeev²³, Susan J Hayflick²⁴

Collaborators

University of Washington Center for Mendelian Genomics:
Michael J Bamshad, Suzanne M Leal, Deborah A Nickerson, Peter Anderson, Marcus Annable, Elizabeth Marchani Blue, Kati J Buckingham, Jennifer Chin, Jessica X Chong, Rodolfo Cornejo Jr, Colleen P Davis, Christopher Frazar, Zongxiao He, Gail P Jarvik, Guillaume Jimenez, Eric Johanson, Tom Kolar, Stephanie A Krauter, Daniel Luksic, Colby T Marvin, Sean McGee, Daniel J McGoldrick, Karynne Patterson, Marcos Perez, Sam W Phillips, Jessica Pijoan, Peggy D Robertson, Regie Santos-Cortez, Aditi Shankar, Krystal Slattery, Kathryn M Shively, Deborah L Siegel, Joshua D Smith, Monica Tackett, Gao Wang, Marc Wegener, Jeffrey M Weiss, Riana I Wernick, Marsha M Wheeler, Qian Yi

Affiliations

¹ 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.
² Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
³ 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.
⁴ 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.
⁵ Cancer Research Center, Pediatric Hemato/oncology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
⁶ Metabolic Disease Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
⁷ Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA.
⁸ Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
⁹ Struthers Parkinson's Center, Golden Valley, MN 55427, USA.
¹⁰ Pediatric Neurology Unit, Edmond and Lily Children's Hospital, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
¹¹ 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.
¹² Child Neurology Department, Foundation IRCCS, Neurological Institute C. Besta, 20133 Milan, Italy.
¹³ Department of Neuropediatrics and Metabolic Diseases; Robert Debré Hospital, 75019 Paris, France.
¹⁴ Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia.
¹⁵ Unit of Molecular Neurogenetics, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
¹⁶ 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.
¹⁷ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
¹⁸ Neurology Department, Princess Margaret Hospital, Perth, WA 6000, Australia.
¹⁹ Diagnostic Imaging Unit, Chaim Sheba Medical Center, 52621 Ramat Gan, Israel.
²⁰ 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.
²¹ 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.
²² 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.
²³ 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: [email protected].
²⁴ 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: [email protected].

Abstract

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.

Publication types

Case Reports

MeSH terms

Basal Ganglia / metabolism
Cells, Cultured
Child
Child, Preschool
Dystonic Disorders / genetics*
Fatty Acids / biosynthesis*
Female
Fibroblasts
Genetic Complementation Test
Humans
Infant
Male
Mitochondria / metabolism*
Mitochondrial Diseases / genetics
Models, Molecular
Mutation*
Mutation, Missense / genetics
Optic Atrophy / genetics*
Oxidoreductases Acting on CH-CH Group Donors / chemistry
Oxidoreductases Acting on CH-CH Group Donors / genetics*
Oxidoreductases Acting on CH-CH Group Donors / metabolism
Pedigree
RNA Splice Sites / genetics
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism

Substances

Fatty Acids
RNA Splice Sites
Oxidoreductases Acting on CH-CH Group Donors
trans-2-enoyl-CoA reductase (NADPH)

Grants and funding

UM1 HG006493/HG/NHGRI NIH HHS/United States