2. Academic Validation
  3. Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency

  • Am J Hum Genet. 2016 Jun 2;98(6):1130-1145. doi: 10.1016/j.ajhg.2016.04.006.
Rikke K J Olsen 1,  Eliška Koňaříková 2,  Teresa A Giancaspero 3,  Signe Mosegaard 4,  Veronika Boczonadi 5,  Lavinija Mataković 6,  Alice Veauville-Merllié 7,  Caterina Terrile 8,  Thomas Schwarzmayr 2,  Tobias B Haack 2,  Mari Auranen 9,  Piero Leone 3,  Michele Galluccio 10,  Apolline Imbard 11,  Purificacion Gutierrez-Rios 12,  Johan Palmfeldt 4,  Elisabeth Graf 8,  Christine Vianey-Saban 7,  Marcus Oppenheim 13,  Manuel Schiff 14,  Samia Pichard 15,  Odile Rigal 16,  Angela Pyle 5,  Patrick F Chinnery 17,  Vassiliki Konstantopoulou 18,  Dorothea Möslinger 18,  René G Feichtinger 6,  Beril Talim 19,  Haluk Topaloglu 20,  Turgay Coskun 21,  Safak Gucer 19,  Annalisa Botta 22,  Elena Pegoraro 23,  Adriana Malena 23,  Lodovica Vergani 23,  Daniela Mazzà 24,  Marcella Zollino 24,  Daniele Ghezzi 25,  Cecile Acquaviva 7,  Tiina Tyni 26,  Avihu Boneh 27,  Thomas Meitinger 2,  Tim M Strom 2,  Niels Gregersen 4,  Johannes A Mayr 6,  Rita Horvath 5,  Maria Barile 28,  Holger Prokisch 2
Affiliations

Affiliations

  • 1 Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and University Hospital, 8200 Aarhus N, Denmark. Electronic address: rikke.olsen@clin.au.dk.
  • 2 Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 3 Department of Biosciences, Biotechnology, and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy.
  • 4 Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and University Hospital, 8200 Aarhus N, Denmark.
  • 5 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
  • 6 Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, 5020 Salzburg, Austria.
  • 7 Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, Centre Hospitalier Universitaire Lyon, 69500 Bron, France.
  • 8 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 9 Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 340 Helsinki, Finland.
  • 10 Department DiBEST (Biology, Ecology, and Earth Sciences), University of Calabria, 87036 Arcavacata di Rende, Italy.
  • 11 Biochemistry Hormonology Laboratory, Robert-Debré Hospital, 75019 Paris, France; Pharmacy Faculty, Paris Sud University, 92019 Chatenay-Malabry, France.
  • 12 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, 41013 Seville, Spain.
  • 13 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London WCIN 3BG, UK.
  • 14 INSERM UMR 1141, Hôpital Robert Debré, 75019 Paris, France; Reference Center for Inherited Metabolic Diseases, Robert-Debré Hospital, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France; Faculté de Médecine Denis Diderot, Université Paris Diderot (Paris 7), 75013 Paris, France.
  • 15 Reference Center for Inherited Metabolic Diseases, Robert-Debré Hospital, Assistance Publique - Hôpitaux de Paris, 75019 Paris, France.
  • 16 Biochemistry Hormonology Laboratory, Robert-Debré Hospital, 75019 Paris, France.
  • 17 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 18 Department of Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
  • 19 Pathology Unit, Department of Pediatrics, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
  • 20 Neurology Unit, Department of Pediatrics, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
  • 21 Metabolism Unit, Department of Pediatrics, Hacettepe University Children's Hospital, 06100 Ankara, Turkey.
  • 22 Medical Genetics Section, Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
  • 23 Neuromuscular Center, Department of Neurosciences, University of Padova, 35129 Padova, Italy.
  • 24 Italy Institute of Medical Genetics, Catholic University of Roma, 00168 Rome, Italy.
  • 25 Molecular Neurogenetics Unit, Foundation IRCCS Neurological Institute C. Besta, 20126 Milan, Italy.
  • 26 Department of Pediatric Neurology, Hospital for Children and Adolescence, Helsinki University Central Hospital, 280 Helsinki, Finland.
  • 27 Murdoch Childrens Research Institute and University of Melbourne, Melbourne, VIC 3010, Australia.
  • 28 Department of Biosciences, Biotechnology, and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy. Electronic address: maria.barile@uniba.it.
PMID: 27259049 DOI: 10.1016/j.ajhg.2016.04.006
Abstract

Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA Sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in Other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.

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