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CLC number: R725.8

On-line Access: 2020-11-05

Received: 2020-06-22

Revision Accepted: 2020-08-16

Crosschecked: 2020-10-13

Cited: 0

Clicked: 2087

Citations:  Bibtex RefMan EndNote GB/T7714


Ting Chen


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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.11 P.885-896


Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency

Author(s):  Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang

Affiliation(s):  Division of Medical Genetics and Genomics, The Children’s Hospital, Zhejiang University School of Medicine / National Clinical Research Center for Child Health, Hangzhou 310052, China; more

Corresponding email(s):   shuqiang@zju.edu.cn, ppjiang@zju.edu.cn

Key Words:  Mitochondrial dysfunction, Very-long-chain acyl-CoA dehydrogenase (VLCAD), β, -Oxidation, Molecular dynamics (MD) simulation

Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang. Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency[J]. Journal of Zhejiang University Science B, 2020, 21(11): 885-896.

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author="Ting Chen, Fan Tong, Xiao-yu Wu, Ling Zhu, Qiu-zi Yi, Jing Zheng, Ru-lai Yang, Zheng-yan Zhao, Xiao-hui Cang, Qiang Shu, Ping-ping Jiang",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency
%A Ting Chen
%A Fan Tong
%A Xiao-yu Wu
%A Ling Zhu
%A Qiu-zi Yi
%A Jing Zheng
%A Ru-lai Yang
%A Zheng-yan Zhao
%A Xiao-hui Cang
%A Qiang Shu
%A Ping-ping Jiang
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 11
%P 885-896
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000339

T1 - Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency
A1 - Ting Chen
A1 - Fan Tong
A1 - Xiao-yu Wu
A1 - Ling Zhu
A1 - Qiu-zi Yi
A1 - Jing Zheng
A1 - Ru-lai Yang
A1 - Zheng-yan Zhao
A1 - Xiao-hui Cang
A1 - Qiang Shu
A1 - Ping-ping Jiang
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 11
SP - 885
EP - 896
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000339

The pathogenesis of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is highly heterogeneous and still unclear. Additional novel variants have been recently detected in the population. The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization. To address this problem, we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency. Marked deficiencies in fatty acid oxidation (FAO) and other mitochondrial defects were observed in cells carrying one of these six variants (c.541C>T, c.863T>G, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A), including reductions in mitochondrial respiratory-chain function and adenosine triphosphate (ATP) production, and increased levels of mitochondrial reactive oxygen species (ROS). Intriguingly, higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress. Moreover, the stability of the mutant homodimer was disturbed, and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics (MD) simulation. The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


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[41]List of electronic supplementary materials

[42]Fig. S1 Variants in VLCAD-deficient patients and their conservation of residues

[43]Fig. S2 Expression levels of HA-tagged VLCAD in cells

[44]Fig. S3 FAO capacity for utilization of exogenous palmitate

[45]Fig. S4 Structural predictions in wild-type and mutant residues

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