Novel variant of ETFDH leading to multiple acyl-CoA dehydrogenase deficiency by promoting protein degradation via ubiquitin proteasome pathway.

Abstract

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive metabolic disease. Patients present with metabolic decompensation, muscle weakness, respiratory failure, and cardiomyopathy. Late-onset MADD is primarily caused by mutations in the ETFDH gene. Here, we report a patient who has been diagnosed with Down syndrome after birth following karyotype analysis and simultaneously carrying compound heterozygous variants of ETFDH (c.3G > C (p. M1?); c.725C > T (p. T242I), which is novel). Further molecular analyses revealed that the novel c.725C > T (p. T242I) mutation enhances the degradation of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) via the ubiquitin proteasome pathway. Five ubiquitin E3 ligases (STUB1, RNF40, UBE3C, CUL3, and CUL1) and one ubiquitin modification site (Cystein, C101) of the ETF-QO were reported in this study. Our study not only expanded the pathogenic variant spectrum of ETFDH gene but also proved that the c.725C > T (p. T242I) will promote protein degradation through ubiquitin proteasome pathway.

• Authors: Bijun Zhang, Yanyan Zhao
• Journal: Clinica chimica acta; international journal of clinical chemistry (Clin Chim Acta) Vol. 530 Pg. 104-112 (May 01 2022) ISSN: 1873-3492 [Electronic] Netherlands
• PMID: 35314173 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Ubiquitin
• STUB1 protein, human
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex

Topics

• Humans
• Multiple Acyl Coenzyme A Dehydrogenase Deficiency (genetics, metabolism)
• Mutation
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Proteolysis
• Ubiquitin (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)