A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3
Open accessAbstract
ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.
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Different substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.
“Different substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.122–124”
From The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis (2015) · cites this paper as [124]
The supplied passages contain no match for the claim. Searches of our copy for ABCD1, ABCD2, ABCD3, dicarboxylic acids, and substrate specificity returned no passages, so I cannot verify the proposed substrate preferences from this source. (LLM, conf=0.65)
Experimental — accuracy not yet measuredA further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.
“A further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.”
From The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis (2015) · cites this paper as [124]
No passage from our indexed copy addresses whether different affinities for very-long-chain fatty acids could explain a lack of compensation in vivo. Searches for the claim’s wording, VLCFA, affinity, and compensation found no relevant passage. (LLM, conf=0.70)
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Cites
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- Authors
- Ferdinandusse, S., Jimenez-Sanchez, G., Koster, J., Denis, S., Van Roermund, C. W., Silva-Zolezzi, I., Moser, A. B., Visser, W. F., Gulluoglu, M., Durmaz, O., Demirkol, M., Waterham, H. R., Gökcay, G., Wanders, R. J. A., & Valle, D.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Kennedy Krieger Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Ferdinandusse, Sacha
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-08-28
- Volume
- 24
- Issue
- 2
- Pages
- 361-370
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2152977496
- Cited by
- 134
- References
- 8
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 10 · 2023: 9 · 2022: 17 · 2021: 9 · 2020: 11 · 2019: 16 · 2018: 16 · 2017: 9 · 2016: 8 · 2015: 11
- FWCI
- 6.41
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- ABCD3, peroxisomal ABC transporters, bile acid synthesis, phytanic acid, peroxisomal import, hepatosplenomegaly, liver disease, peroxisome biogenesis disorders
- MeSH terms
- Animals, Bile Acids and Salts, Fatty Acids, Female, Humans, Liver Diseases, Male, Mice, Knockout, ATP-Binding Cassette Transporters, Peroxisomes, Mice
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