期刊
JOURNAL OF MEDICAL GENETICS
卷 54, 期 5, 页码 330-337出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2016-104132
关键词
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资金
- Marie Curie Initial Training Networks (ITN) action [FP7-2012-PERFUME-316-723]
- Biotechnology and Biological Sciences Research Council [BB/K006231/1, BB/N01541X/1]
- BBSRC [BB/N01541X/1, BB/K006231/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N01541X/1, BB/K006231/1] Funding Source: researchfish
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.
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