MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder PMID: 27817865

ADC Targets in Oncology

2026-04-10

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.

Gali Heimer ¹ , Juha M Kerätär ² , Lisa G Riley ³ , Shanti Balasubramaniam ⁴ , Eran Eyal ⁵ , Laura P Pietikäinen ² , J Kalervo Hiltunen ² , Dina Marek-Yagel ⁶ , Jeffrey Hamada ⁷ , Allison Gregory ⁷ , Caleb Rogers ⁷ , Penelope Hogarth ⁸ , Martha A Nance ⁹ , Nechama Shalva ⁶ , Alvit Veber ⁶ , Michal Tzadok ¹⁰ , Andreea Nissenkorn ¹¹ , Davide Tonduti ¹² , Florence Renaldo ¹³ , University of Washington Center for Mendelian Genomics , Ichraf Kraoua ¹⁴ , Celeste Panteghini ¹⁵ , Lorella Valletta ¹⁵ , Barbara Garavaglia ¹⁵ , Mark J Cowley ¹⁶ , Velimir Gayevskiy ¹⁷ , Tony Roscioli ¹⁶ , Jonathon M Silberstein ¹⁸ , Chen Hoffmann ¹⁹ , Annick Raas-Rothschild ²⁰ , Valeria Tiranti ¹⁵ , Yair Anikster ²¹ , John Christodoulou ²² , Alexander J Kastaniotis ² , Bruria Ben-Zeev ²³ , Susan J Hayflick ²⁴

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.