CD1 Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy
Open accessAbstract
X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ² = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD.
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Modifier-gene variants likely exist but may only be identified if agnostic whole-genome analysis studies recruit and compare thousands of well-defined cALD and pure AMN patients.
“Unless they are relatively common and have a major phenotypic effect, modifier-gene variants (likely to exist) may only be identified if agnostic whole-genome analysis studies are able to recruit and compare thousands of well-defined patients with cALD with thousands of patients with “pure” AMN [117,118].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [118]
The Discussion (page unavailable) says genetic variants may contribute to X-ALD phenotypic differences and that the candidate-gene strategy has major limitations. The Methods describe comparing well-defined childhood cerebral ALD and “pure” AMN groups. The paper does not say that identifying modifier variants requires agnostic whole-genome analysis or thousands of patients in each group. (LLM, conf=0.85)
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Cites
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X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects
Kemp, S., Berger, J., & Aubourg, P. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.03.012 · Cited by 283 · see citing works
Self-citationBerger, J., Wiesinger, C., & Eichler, F. (2015) · The Application of Clinical Genetics · doi:10.2147/tacg.s49590 · Cited by 140 · see citing works
Self-citationvan Engen, C. E., Ofman, R., Dijkstra, I. M. E., van Goethem, T. J., Verheij, E., Varin, J., Vidaud, M., Wanders, R. J. A., Aubourg, P., Kemp, S., et al. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.07.006 · Cited by 26 · see citing works
Self-citationRevisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Barbier, M., Sabbagh, A., Kasper, E., Asheuer, M., Ahouansou, O., Pribill, I., Forss-Petter, S., Vidaud, M., Berger, J., & Aubourg, P.
- Affiliations
- Inserm (FR)
- Sorbonne Paris Cité (FR)
- Medical University of Vienna (AT)
- Corresponding author
- Barbier, Mathieu
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-01-12
- Volume
- 7
- Issue
- 1
- Pages
- e29872
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3257241
- OpenAlex
- W2067206553
- Cited by
- 18
- References
- 1
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- European Commission (241622)
- Institut National de la Santé et de la Recherche Médicale
- Vienna Science and Technology Fund (LS154)
- Universität Wien
- Medizinische Universität Wien
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- X-linked adrenoleukodystrophy, CD1d, genotype-phenotype correlation, adrenomyeloneuropathy, childhood cerebral adrenoleukodystrophy, genetic modifiers, very long chain fatty acids, lipid antigen presentation, single nucleotide polymorphisms, ABCD1
- MeSH terms
- Adrenoleukodystrophy, Alleles, Base Sequence, Humans, Middle Aged, Phenotype, Case-Control Studies, Sequence Analysis, DNA, Antigens, CD1, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Antigens, CD1d, Genetic Loci, Genetic Association Studies
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