Ferdinandusse Sacha, Falkenberg Kim D, Koster Janet, Mooyer Petra A, Jones Richard, van Roermund Carlo W T, Pizzino Amy, Schrader Michael, Wanders Ronald J A, Vanderver Adeline, Waterham Hans R
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
Kennedy Krieger Institute, Baltimore, Maryland, USA.
J Med Genet. 2017 May;54(5):330-337. doi: 10.1136/jmedgenet-2016-104132. Epub 2016 Oct 31.
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 in another patient and studied the consequences of the ACBD5 defect in patient material and in ACBD5-deficient HeLa cells to uncover this role.
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.
We identified a homozygous deleterious indel mutation in , 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 β-oxidation. No effect on pexophagy was found.
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 β-oxidation. Accordingly, ACBD5 deficiency is a novel single peroxisomal enzyme deficiency caused by impaired VLCFA metabolism, leading to retinal dystrophy and white matter disease.
含酰基辅酶A结合结构域蛋白5（ACBD5）是一种过氧化物酶体膜蛋白，具有胞质酰基辅酶A结合结构域。由于其酰基辅酶A结合结构域，ACBD5被认为作为酰基辅酶A酯的细胞内载体发挥作用。此外，有人提出ACBD5在过氧化物酶体自噬中发挥作用。然而，ACBD5在过氧化物酶体代谢和/或功能中的精确作用尚未确定。此前，在三名患有视网膜营养不良和白质疾病的兄弟姐妹中发现了遗传性ACBD5缺陷。我们在另一名患者中鉴定出一种致病突变，并在患者材料和ACBD5缺陷的HeLa细胞中研究了ACBD5缺陷的后果，以揭示这一作用。
我们研究了一名患有进行性脑白质营养不良、综合征性腭裂、共济失调和视网膜营养不良的女孩。我们在患者材料和通过CRISPR-Cas9基因组编辑产生的ACBD5缺陷的HeLa细胞中进行了生化、细胞生物学和分子研究。
我们在[具体基因]中鉴定出一个纯合有害插入缺失突变，导致患者体内ACBD5蛋白完全缺失。我们的研究表明，由于过氧化物酶体β氧化受损，ACBD5缺陷导致极长链脂肪酸（VLCFA）积累。未发现对过氧化物酶体自噬有影响。
我们的研究强烈表明，ACBD5在将C26-辅酶A隔离在细胞质中起着重要作用，从而促进其转运到过氧化物酶体并随后进行β氧化。因此，ACBD5缺陷是一种由VLCFA代谢受损引起的新型单一过氧化物酶体酶缺陷，导致视网膜营养不良和白质疾病。
