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dc.contributor.authorFerdinandusse, S, SF
dc.contributor.authorFalkenberg, K, KF
dc.contributor.authorKoster, J, JK
dc.contributor.authorMooyer, PM
dc.contributor.authorJones, R, RJ
dc.contributor.authorvan Roermund, C, C
dc.contributor.authorPizzino, A, AP
dc.contributor.authorSchrader, M
dc.contributor.authorWanders, R, RW
dc.contributor.authorVanderver, A, AV
dc.contributor.authorWaterham, H, HW
dc.date.accessioned2016-10-12T08:20:50Z
dc.date.issued2016-10-31
dc.description.abstractBackground 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 longchain 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 and leading to retinal dystrophy and white matter disease.en_GB
dc.description.sponsorshipSupported in part by funding through the Marie Curie Initial Training Networks (ITN) action to KDF, MS and HRW (FP7-2012-PERFUME-316723). MS is supported by the Biotechnology and Biological Sciences Research Council (BB/K006231/1; BB/N01541X/1).en_GB
dc.identifier.citationPublished Online First 31 October 2016en_GB
dc.identifier.doi10.1136/jmedgenet-2016-104132
dc.identifier.urihttp://hdl.handle.net/10871/23869
dc.language.isoenen_GB
dc.publisherBMJ Publishing Groupen_GB
dc.rightsThis is the author accepted manuscript. The final version is available from BMJ Publishing Group via the DOI in this record.
dc.subjectPeroxisomal disorderen_GB
dc.subjectperoxisomal beta-oxidationen_GB
dc.subjectpexophagyen_GB
dc.subjectvery long-chain fatty acidsen_GB
dc.subjectacyl-CoA binding domain containing protein 5en_GB
dc.subjectperoxisomal single enzyme deficiencyen_GB
dc.titleACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolismen_GB
dc.typeArticleen_GB
dc.identifier.issn0306-6800
dc.identifier.journalJournal of Medical Ethicsen_GB


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