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

Näytä kaikki kuvailutiedot



Pysyväisosoite

http://hdl.handle.net/10138/224053

Lähdeviite

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

Julkaisun nimi: Riboflavin-Responsive and -Non-responsive Mutations in FAD Synthase Cause Multiple Acyl-CoA Dehydrogenase and Combined Respiratory-Chain Deficiency
Tekijä: Olsen, Rikke K. J.; Konarikova, Eliska; Giancaspero, Teresa A.; Mosegaard, Signe; Boczonadi, Veronika; Matakovic, Lavinija; Veauville-Merllie, Alice; Terrile, Caterina; Schwarzmayr, Thomas; Haack, Tobias B.; Auranen, Mari; Leone, Piero; Galluccio, Michele; Imbard, Apolline; Gutierrez-Rios, Purificacion; Palmfeldt, Johan; Graf, Elisabeth; Vianey-Saban, Christine; Oppenheim, Marcus; Schiff, Manuel; Pichard, Samia; Rigal, Odile; Pyle, Angela; Chinnery, Patrick F.; Konstantopoulou, Vassiliki; Moslinger, Dorothea; Feichtinger, Rene G.; Talim, Beril; Topaloglu, Haluk; Coskun, Turgay; Gucer, Safak; Botta, Annalisa; Pegoraro, Elena; Malena, Adriana; Vergani, Lodovica; Mazza, Daniela; Zollino, Marcella; Ghezzi, Daniele; Acquaviva, Cecile; Tyni, Tiina; Boneh, Avihu; Meitinger, Thomas; Strom, Tim M.; Gregersen, Niels; Mayr, Johannes A.; Horvath, Rita; Barile, Maria; Prokisch, Holger
Tekijän organisaatio: Clinicum
Neurologian yksikkö
Children's Hospital
Lastenneurologian yksikkö
HUS Children and Adolescents
Päiväys: 2016-06-02
Kieli: eng
Sivumäärä: 16
Kuuluu julkaisusarjaan: American Journal of Human Genetics
ISSN: 0002-9297
DOI-tunniste: https://doi.org/10.1016/j.ajhg.2016.04.006
URI: http://hdl.handle.net/10138/224053
Tiivistelmä: 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.
Avainsanat: ELECTRON-TRANSFER FLAVOPROTEIN
VIALETTO-VAN LAERE
OVER-EXPRESSION
FUNCTIONAL-CHARACTERIZATION
ESCHERICHIA-COLI
ISOFORM 2
MITOCHONDRIA
DISEASE
SYNTHETASE
COFACTORS
3111 Biomedicine
Vertaisarvioitu: Kyllä
Pääsyrajoitteet: openAccess
Rinnakkaistallennettu versio: publishedVersion


Tiedostot

Latausmäärä yhteensä: Ladataan...

Tiedosto(t) Koko Formaatti Näytä
1_s2.0_S000292971630101X_main.pdf 2.205MB PDF Avaa tiedosto

Viite kuuluu kokoelmiin:

Näytä kaikki kuvailutiedot