title: ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism.
abstract: 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 inACBD5in 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 inACBD5, 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.
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Sacha
authors: S
authors: Ferdinandusse
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Kim D
authors: KD
authors: Falkenberg
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Janet
authors: J
authors: Koster
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Petra A
authors: PA
authors: Mooyer
authors: Kennedy Krieger Institute, Baltimore, Maryland, USA.
authors: Richard
authors: R
authors: Jones
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Carlo W T
authors: CWT
authors: van Roermund
authors: Department of Neurology, Children's National Health System, Washington DC, USA.
authors: Amy
authors: A
authors: Pizzino
authors: College of Life and Environmental Sciences, Biosciences, University of Exeter, Exeter, Devon, UK.
authors: Michael
authors: M
authors: Schrader
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Ronald J A
authors: RJA
authors: Wanders
authors: Department of Neurology, Children's National Health System, Washington DC, USA.
authors: Adeline
authors: A
authors: Vanderver
authors: Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors: Hans R
authors: HR
authors: Waterham
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000378:metabolism; D001343:Autophagy; D002675:Child, Preschool; D018076:DNA, Complementary / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005816:Genetic Complementation Test; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism*; D012867:Skin / Q000473:pathology
chemical_list: C548478:ACBD5 protein, human; D000214:Acyl Coenzyme A; D048868:Adaptor Proteins, Signal Transducing; D018076:DNA, Complementary; D005227:Fatty Acids; D008565:Membrane Proteins
keywords: acyl-CoA binding domain containing protein 5; peroxisomal beta-oxidation; peroxisomal single enzyme deficiency; pexophagy; very long-chain fatty acids