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Suppl. Mater.: 

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

 ORCID:

Ting Chen

https://orcid.org/0000-0002-0530-675X

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

http://doi.org/10.1631/jzus.B2000339


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.

@article{title="Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency",
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",
volume="21",
number="11",
pages="885-896",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2000339"
}

%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

TY - JOUR
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


Abstract: 
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.

极长链酰基辅酶A脱氢酶缺乏症ACADVL基因新发突变导致线粒体功能障碍

目的:鉴定并阐述6个ACADVL新发突变的对细胞和分子功能的影响,为后期分子诊断和临床病例管理提供科学依据.
创新点:本文从分子功能和结构的角度阐述6个新位点对蛋白和细胞功能的不同影响.
方法:通过体外构建突变载体建立各突变的过表达细胞系,检测各细胞系脂肪酸代谢能力、线粒体呼吸链功能、线粒体产三磷酸腺苷(ATP)能力、活性氧(ROS)和凋亡水平.同时检测了新发突变对蛋白二聚体稳定性的影响并用分子动力学模拟了突变蛋白构像的改变.
结论:突变(c.541C>T、c.863T>G、c.895A>G、c.1238T>C、c.1276G>A和c.1505T>A)过表达细胞系均表现出脂肪酸代谢障碍,线粒体呼吸链功能障碍,ATP产生水平下降和线粒体ROS水平上升.在无糖条件下,各细胞系的凋亡水平上升.各突变影响了极长链酰基辅酶A脱氢酶(VLCAD)蛋白二聚体的稳定性,分子动力学模拟预测每个突变均会导致VLCAD蛋白结构的发生重要构象变化.

关键词:线粒体功能障碍;极长链酰基辅酶A脱氢酶缺乏症;β氧化;分子动力学模拟

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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