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

Rikke K.J. Olsen, Eliška Koňaříková, Teresa A. Giancaspero, Signe Mosegaard, Veronika Boczonadi, Lavinija Mataković, Alice Veauville-Merllié, Caterina Terrile, Thomas Schwarzmayr, Tobias B. Haack, Mari Auranen, Piero Leone, Michele Galluccio, Apolline Imbard, Purificacion Gutierrez-Rios, Johan Palmfeldt, Elisabeth Graf, Christine Vianey-Saban, Marcus Oppenheim, Manuel SchiffSamia Pichard, Odile Rigal, Angela Pyle, Patrick F. Chinnery, Vassiliki Konstantopoulou, Dorothea Möslinger, René G. Feichtinger, Beril Talim, Haluk Topaloglu, Turgay Coskun, Safak Gucer, Annalisa Botta, Elena Pegoraro, Adriana Malena, Lodovica Vergani, Daniela Mazzà, Marcella Zollino, Daniele Ghezzi, Cecile Acquaviva, Tiina Tyni, Avihu Boneh, Thomas Meitinger, Tim M. Strom, Niels Gregersen, Johannes A. Mayr, Rita Horvath, Maria Barile, Holger Prokisch

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113 Scopus citations


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.

Original languageEnglish
Pages (from-to)1130-1145
Number of pages16
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - 2 Jun 2016


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