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

TitleRiboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency.
Publication TypeJournal Article
Year of Publication2016
AuthorsOlsen, RKJ, Koňaříková, E, Giancaspero, TA, Mosegaard, S, Boczonadi, V, Mataković, L, Veauville-Merllié, A, Terrile, C, Schwarzmayr, T, Haack, TB, Auranen, M, Leone, P, Galluccio, M, Imbard, A, Gutierrez-Rios, P, Palmfeldt, J, Graf, E, Vianey-Saban, C, Oppenheim, M, Schiff, M, Pichard, S, Rigal, O, Pyle, A, Chinnery, PF, Konstantopoulou, V, Möslinger, D, Feichtinger, RG, Talim, B, Topaloglu, H, Coskun, T, Gucer, S, Botta, A, Pegoraro, E, Malena, A, Vergani, L, Mazzà, D, Zollino, M, Ghezzi, D, Acquaviva, C, Tyni, T, Boneh, A, Meitinger, T, Strom, TM, Gregersen, N, Mayr, JA, Horvath, R, Barile, M, Prokisch, H
JournalAm J Hum Genet
Volume98
Issue6
Pagination1130-45
Date Published2016 Jun 02
ISSN1537-6605
KeywordsAdult, Blotting, Western, Case-Control Studies, Cells, Cultured, Electron Transport, Female, Fibroblasts, Flavin-Adenine Dinucleotide, Frameshift Mutation, Gene Expression Profiling, Humans, Infant, Infant, Newborn, Liver, Male, Mitochondrial Diseases, Multiple Acyl Coenzyme A Dehydrogenase Deficiency, Muscle, Skeletal, Mutagenesis, Site-Directed, Nucleotidyltransferases, Protein Binding, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Riboflavin, RNA, Messenger, Skin, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Vitamin B Complex, Young Adult
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.

DOI10.1016/j.ajhg.2016.04.006
Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2016.04.006
PubMed ID27259049
PubMed Central IDPMC4908180
Grant List309548 / / European Research Council / International
G1000848 / / Medical Research Council / United Kingdom