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- Title
ETFDH Mutations and Flavin Adenine Dinucleotide Homeostasis Disturbance Are Essential for Developing Riboflavin-Responsive Multiple Acyl-Coenzyme A Dehydrogenation Deficiency.
- Authors
Xu, Jingwen; Li, Duoling; Lv, Jingwei; Xu, Xuebi; Wen, Bing; Lin, Pengfei; Liu, Fuchen; Ji, Kunqian; Shan, Jingli; Li, Honghao; Li, Wei; Zhao, Yuying; Zhao, Dandan; Pok, Joo Y.; Yan, Chuanzhu
- Abstract
<bold>Objective: </bold>Riboflavin-responsive multiple acyl-coenzyme A dehydrogenation deficiency (RR-MADD) is an inherited fatty acid metabolism disorder mainly caused by genetic defects in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). The variant ETF:QO protein folding deficiency, which can be corrected by therapeutic dosage of riboflavin supplement, has been identified in HEK-293 cells and is believed to be the molecular mechanism of this disease. To verify this hypothesis in vivo, we generated Etfdh (h)A84T knockin (KI) mice.<bold>Methods: </bold>Tissues from these mice as well as muscle biopsies and fibroblasts from 7 RR-MADD patients were used to examine the flavin adenine dinucleotide (FAD) concentration and ETF:QO protein amount.<bold>Results: </bold>All of the homozygous KI mice (Etfdh (h)A84T/(h)A84T , KI/KI) were initially normal. After being given a high-fat and vitamin B2 -deficient (HF-B2 D) diet for 5 weeks, they developed weight loss, movement ability defects, lipid storage in muscle and liver, and elevated serum acyl-carnitine levels, which are clinically and biochemically similar to RR-MADD patients. Both ETF:QO protein and FAD concentrations were significantly decreased in tissues of HF-B2 D-KI/KI mice and in cultured fibroblasts from RR-MADD patients. After riboflavin treatment, ETF:QO protein increased in proportion to elevated FAD concentrations, but not related to mRNA levels. These results were further confirmed in cultured fibroblasts from RR-MADD patients.<bold>Interpretation: </bold>For the first time, we successfully developed a RR-MADD mice model and confirmed that FAD homeostasis disturbances played a crucial role on the pathomechanism of RR-MADD in this mouse model and culture cells from patients. Supplementation of riboflavin may stabilize variant ETF:QO protein by rebuilding FAD homeostasis. Ann Neurol 2018;84:667-681.
- Subjects
ADENINE nucleotides; VITAMIN B2; NEURODEGENERATION; GENE expression; GENETIC mutation
- Publication
Annals of Neurology, 2018, Vol 84, Issue 5, p659
- ISSN
0364-5134
- Publication type
journal article
- DOI
10.1002/ana.25338