ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. Issue 5 (31st October 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of medical genetics. Volume 54:Issue 5(2017)
• Page Start: 330
• Page End: 337
• Publication Date: 2016-10-31
• Subjects: peroxisomal single enzyme deficiency -- peroxisomal beta-oxidation -- pexophagy -- very long-chain fatty acids -- acyl-CoA binding domain containing protein 5; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2016-104132
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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 β-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 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.