Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants
Fluxomic evidence for impaired contribution of short-chain acyl-CoA dehydrogenase to mitochondrial palmitate β-oxidation in symptomatic patients with ACADS gene susceptibility variants
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DOI：
10.1016/j.cca.2017.05.026
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发表时间：
2017-08-01
影响因子：
5
通讯作者：
Vamecq, Joseph
中科院分区：
文献类型：
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作者：
Dessein, Anne-Frederique;Fontaine, Monique;Vamecq, Joseph
背景资料：尽管ACADS（芳基辅酶A脱氢酶，短链）基因易感性变体（c.511C > T和c.625G > A）被认为是非致病性的，但已知编码的蛋白质表现出改变的动力学。然而，它们是否可能影响整体脂肪酸β-氧化仍然不清楚。方法：通过与氘代棕榈酸酯孵育的全血样品从头生物合成酰基肉毒碱（16-H-2（3），15-H-2（2）-棕榈酸酯）适合作为通量组学探索以区分正常和破坏的β-氧化，具有不同链长的酰基肉毒碱的异常分布和比率指示酶阻断的位点。测定在301个对照组之间的比率氘丁酰肉碱和氘C2至C14酰基肉毒碱的总和在这里作为参考值，以说明具体的功能SCAD损伤的患者解决的临床和/或生物学怀疑的β-oxidation disorder.Results：功能SCAD损伤被发现在39例。接受后续基因研究的27例患者均为ACADS突变阳性。27例患者中有26例c.625G > A变异阳性。27例患者中有23例携带易感性变异作为唯一的ACADS改变（18例纯合子和3例杂合子为c.625G > A，2例复合杂合子为c.625G > A/c.511C > T）。结论：我们目前对SCAD的fluxomic评估表明ACADS易感性变异和异常β-氧化之间存在联系，与这些变异的已知改变动力学一致。
Background: Despite ACADS (aryl-CoA dehydrogenase, short-chain) gene susceptibility variants (c.511C > T and c.625G > A) are considered to be non-pathogenic, encoded proteins are known to exhibit altered kinetics. Whether or not, they might affect overall fatty acid beta-oxidation still remains, however, unclear.Methods: De novo biosynthesis of acylcarnitines by whole blood samples incubated with deuterated palmitate (16-H-2(3),15-H-2(2)-palmitate) is suitable as a fluxomic exploration to distinguish between normal and disrupted beta-oxidation, abnormal profiles and ratios of acylcarnitines with different chain-lengths being indicative of the site for enzymatic blockade. Determinations in 301 control subjects of ratios between deuterated butyrylcarnitine and sum of deuterated C2 to C14 acylcarnitines served here as reference values to state specifically functional SCAD impairment in patients addressed for clinical and/or biological suspicion of a beta-oxidation disorder.Results: Functional SCAD impairment was found in 39 patients. The 27 patients accepting subsequent gene studies were all positive for ACADS mutations. Twenty-six of 27 patients were positive for c.625G > A variant. Twenty-three of 27 patients harbored susceptibility variants as sole ACADS alterations (18 homozygous and 3 heterozygous for c.625G > A, 2 compound heterozygous for c.625G > A/c.511C > T).Conclusion: Our present fluxomic assessment of SCAD suggests a link between ACADS susceptibility variants and abnormal beta-oxidation consistent with known altered kinetics of these variants.