ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism
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DOI：
10.1136/jmedgenet-2016-104132
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发表时间：
2017-05-01
影响因子：
4
通讯作者：
Waterham, Hans R.
中科院分区：
文献类型：
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作者：
Ferdinandusse, Sacha;Falkenberg, Kim D.;Waterham, Hans R.
研究背景酰基辅酶A结合域蛋白5（Acyl-CoA binding domain containing protein 5，ACBD 5）是一种具有胞浆酰基辅酶A结合域的过氧化物酶体膜蛋白。由于其酰基辅酶A结合结构域，ACBD 5被认为是酰基辅酶A酯的细胞内载体。此外，ACBD 5在pexophagy中的作用也被提出。然而，ACBD 5在过氧化物酶体代谢和/或功能中的确切作用尚未确定。此前，在三名患有视网膜营养不良和白色物质疾病的兄弟姐妹中发现了遗传性ACBD 5缺陷。我们确定了一个致病突变ACBD 5在另一名患者和研究的后果ACBD 5缺陷的患者材料和ACBD 5缺陷的HeLa细胞，以揭示这一role.Methods我们研究了一个女孩谁提出了进行性脑白质营养不良，腭裂综合征，共济失调和视网膜营养不良。我们对患者材料和通过CRISPR-Cas9基因组编辑产生的ACBD 5缺陷型HeLa细胞进行了生物化学、细胞生物学和分子研究。结果我们鉴定了ACBD 5中的纯合有害indel突变，导致患者ACBD 5蛋白完全丢失。我们的研究表明，ACBD 5缺乏导致非常长链脂肪酸（VLCFA）的积累，由于受损的过氧化物酶体β-氧化。没有影响pexophagywasfound.Conclusions我们的调查强烈表明，ACBD 5在螯合C26-CoA在胞质溶胶中起着重要的作用，从而有利于运输到过氧化物酶体和随后的β-氧化。因此，ACBD 5缺乏是由VLCFA代谢受损引起的新的单一过氧化物酶体酶缺乏，导致视网膜营养不良和白色疾病。
Background Acyl-CoA binding domain containing protein 5 (ACBD5) is a peroxisomal membrane protein with a cytosolic acyl-CoA binding domain. Because of its acyl-CoA binding domain, ACBD5 has been assumed to function as an intracellular carrier of acyl-CoA esters. In addition, a role for ACBD5 in pexophagy has been suggested. However, the precise role of ACBD5 in peroxisomal metabolism and/or functioning has not yet been established. Previously, a genetic ACBD5 deficiency was identified in three siblings with retinal dystrophy and white matter disease. We identified a pathogenic mutation in ACBD5 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role.Methods We studied a girl who presented with progressive leukodystrophy, syndromic cleft palate, ataxia and retinal dystrophy. We performed biochemical, cell biological and molecular studies in patient material and in ACBD5-deficient HeLa cells generated by CRISPR-Cas9 genome editing.Results We identified a homozygous deleterious indel mutation in ACBD5, leading to complete loss of ACBD5 protein in the patient. Our studies showed that ACBD5 deficiency leads to accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal beta-oxidation. No effect on pexophagy was found.Conclusions Our investigations strongly suggest that ACBD5 plays an important role in sequestering C26-CoA in the cytosol and thereby facilitates transport into the peroxisome and subsequent beta-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.