期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 98, 期 6, 页码 1130-1145出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.04.006
关键词
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资金
- Aarhus County Research Initiative
- Danish Council of Independent Medical Research [4004-00548]
- John and Birthe Meyer Foundation
- European Commission [GA 317433]
- Neuromuscular Research Association Angela Maria Nieddu
- Telethon Genetic BioBank [GTB12001D]
- EuroBioBank network
- Telethon Foundation [GGP15041]
- Italian Ministry of Health [GR2010-2316392]
- Programma Operativo Nazionale Ricerca e Competitivita [01_00937]
- European Research Council [309548]
- UK Medical Research Council [G1000848]
- German Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for Mitochondrial Disorders (mitoNET) [01GM1113C]
- E-Rare project GENOMIT [01GM1207]
- Juniorverbund in der Systemmedizin mitOmics [FKZ 01ZX1405C]
- MRC [G1000848] Funding Source: UKRI
- Medical Research Council [MR/N027302/1, G1000848] Funding Source: researchfish
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.
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