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

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dc.contributor.author Olsen, Rikke K. J.
dc.contributor.author Konarikova, Eliska
dc.contributor.author Giancaspero, Teresa A.
dc.contributor.author Mosegaard, Signe
dc.contributor.author Boczonadi, Veronika
dc.contributor.author Matakovic, Lavinija
dc.contributor.author Veauville-Merllie, Alice
dc.contributor.author Terrile, Caterina
dc.contributor.author Schwarzmayr, Thomas
dc.contributor.author Haack, Tobias B.
dc.contributor.author Auranen, Mari
dc.contributor.author Leone, Piero
dc.contributor.author Galluccio, Michele
dc.contributor.author Imbard, Apolline
dc.contributor.author Gutierrez-Rios, Purificacion
dc.contributor.author Palmfeldt, Johan
dc.contributor.author Graf, Elisabeth
dc.contributor.author Vianey-Saban, Christine
dc.contributor.author Oppenheim, Marcus
dc.contributor.author Schiff, Manuel
dc.contributor.author Pichard, Samia
dc.contributor.author Rigal, Odile
dc.contributor.author Pyle, Angela
dc.contributor.author Chinnery, Patrick F.
dc.contributor.author Konstantopoulou, Vassiliki
dc.contributor.author Moslinger, Dorothea
dc.contributor.author Feichtinger, Rene G.
dc.contributor.author Talim, Beril
dc.contributor.author Topaloglu, Haluk
dc.contributor.author Coskun, Turgay
dc.contributor.author Gucer, Safak
dc.contributor.author Botta, Annalisa
dc.contributor.author Pegoraro, Elena
dc.contributor.author Malena, Adriana
dc.contributor.author Vergani, Lodovica
dc.contributor.author Mazza, Daniela
dc.contributor.author Zollino, Marcella
dc.contributor.author Ghezzi, Daniele
dc.contributor.author Acquaviva, Cecile
dc.contributor.author Tyni, Tiina
dc.contributor.author Boneh, Avihu
dc.contributor.author Meitinger, Thomas
dc.contributor.author Strom, Tim M.
dc.contributor.author Gregersen, Niels
dc.contributor.author Mayr, Johannes A.
dc.contributor.author Horvath, Rita
dc.contributor.author Barile, Maria
dc.contributor.author Prokisch, Holger
dc.date.accessioned 2017-09-14T09:55:25Z
dc.date.available 2021-12-17T18:49:06Z
dc.date.issued 2016-06-02
dc.identifier.citation Olsen , R K J , Konarikova , E , Giancaspero , T A , Mosegaard , S , Boczonadi , V , Matakovic , L , Veauville-Merllie , A , Terrile , C , Schwarzmayr , T , Haack , T B , 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 , P F , Konstantopoulou , V , Moslinger , D , Feichtinger , R G , 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 , T M , Gregersen , N , Mayr , J A , Horvath , R , Barile , M & Prokisch , H 2016 , ' Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency ' , American Journal of Human Genetics , vol. 98 , no. 6 , pp. 1130-1145 . https://doi.org/10.1016/j.ajhg.2016.04.006
dc.identifier.other PURE: 65751782
dc.identifier.other PURE UUID: 6a396d6c-6f37-4f00-b015-538f65dc3d0d
dc.identifier.other WOS: 000377286000008
dc.identifier.other Scopus: 84971568098
dc.identifier.uri http://hdl.handle.net/10138/224053
dc.description.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. en
dc.format.extent 16
dc.language.iso eng
dc.relation.ispartof American Journal of Human Genetics
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ISOFORM 2
dc.subject DISEASE
dc.subject SYNTHETASE
dc.subject COFACTORS
dc.subject 3111 Biomedicine
dc.title Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency en
dc.type Article
dc.contributor.organization Clinicum
dc.contributor.organization Neurologian yksikkö
dc.contributor.organization Children's Hospital
dc.contributor.organization Lastenneurologian yksikkö
dc.contributor.organization HUS Children and Adolescents
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.ajhg.2016.04.006
dc.relation.issn 0002-9297
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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