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

Lookup NU author(s): Dr Veronika Boczonadi, Dr Angela Pyle, Professor Patrick Chinnery, Professor Tiina Tyni, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Olsen RKJ, Konarikova E, Giancaspero TA, Mosegaard S, Boczonadi V, Matakovic L, Veauville-Merllie 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, Moslinger D, Feichtinger RG, Talim B, Topaloglu H, Coskun T, Gucer S, Botta A, Pegoraro E, Malena A, Vergani L, Mazza 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

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2016

Volume: 98

Issue: 6

Pages: 1130-1145

Online publication date: 02/06/2016

Acceptance date: 13/04/2016

Date deposited: 08/08/2016

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2016.04.006


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Funder referenceFunder name
EuroBioBank network
John and Birthe Meyer Foundation
Aarhus County Research Initiative
Neuromuscular Research Association Angela Maria Nieddu
01GM1113CGerman Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for Mitochondrial Disorders (mitoNET)
01_00937Programma Operativo Nazionale "Ricerca e Competitivita"
01GM1207E-Rare project GENOMIT
4004-00548Danish Council of Independent Medical Research
309548European Research Council
FKZ 01ZX1405CJuniorverbund in der Systemmedizin "mitOmics"
G1000848UK Medical Research Council
GA 317433European Commission
GR2010-2316392Italian Ministry of Health
GGP15041Telethon Foundation
GTB12001DTelethon Genetic BioBank