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Cited by 190Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchHereditary Neurological Disorders

X-linked adrenoleukodystrophy: Genes, mutations, and phenotypes

Smith, Kirby D., Kemp, Stephan, Braiterman, Lelita T., Lu, Jyh-Feng, Wei, He-Ming, Geraghty, Michael, Stetten, Gail, Bergin, James S. +2 more·1999·Neurochemical Research
DOI 10.1023/a:1022535930009
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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous features of the disease. However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.

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Crossref · 10.1023/a:1022535930009

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  • Large deletions or frameshift mutations leading to complete absence of ALDP can be associated with mild AMN phenotypes as well as with cALD.

    “Beyond the “one gene, one disease” paradigm, large deletions or frameshift mutations leading to the complete absence of the ALD protein (ALDP) can be associated with mild AMN phenotypes as well as with cALD [102].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [102]

  • ABCD1 mutations do not govern the individual variability of clinical manifestations in X-ALD.

    “More strikingly than in many single-gene diseases, ABCD1 mutations do not govern the individual variability of clinical manifestations.”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [102]

  • The 1415delAG mutation has been identified in patients with all possible X-ALD phenotypes.

    “The mutation 1415delAG has been identified in patients with all possible X-ALD phenotypes [Kemp et al., 1994;Smith et al., 1999].”

    From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Smith et al., 1999

  • X-ALD fibroblasts transfected with an ALDP deletion mutant lacking amino acids 693 to 745 had similar β-oxidation activity as X-ALD fibroblasts transfected with wild type ALDP cDNA, and deletion of the 52 carboxyl-terminal amino acids did not affect protein stability.

    “Smith and coworkers [1999] demonstrated that X-ALD fibroblasts transfected with a cDNA construct encoding an ALDP deletion mutant that lacks amino acids 693 to 745 (ALDPdel693-745) had similar β-oxidation activity as X-ALD fibroblasts transfected with a wild type ALDP cDNA construct.In addition, the deletion of the 52 carboxyl-terminal amino acids did not affect the stability of the protein.”

    From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Smith et al., 1999

  • In vitro, homodimerization and heterodimerization of the carboxyl-terminal halves of ALDP, ALDRP, and PMP70 have been demonstrated.

    “In vitro, homodimerization, and heterodimerization of the carboxyl-terminal halves of ALDP, ALDRP, and PMP70 have been demonstrated using co-immunoprecipitation assays and the yeast two-hybrid system [Smith et al., 1999;Liu et al., 1999].”

    From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Smith et al., 1999

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Authors
Smith, K. D., Kemp, S., Braiterman, L. T., Lu, J.-F., Wei, H.-M., Geraghty, M., Stetten, G., Bergin, J. S., Pevsner, J., & Watkins, P. A.
Affiliations
  • Kennedy Krieger Institute (US)
  • Johns Hopkins University (US)
Corresponding author
Smith, Kirby D.
ORCID
Venue
Neurochemical Research
Publisher
Springer Science and Business Media LLC
Published
1999-04
Volume
24
Issue
4
Pages
521-535
ISSN
  • 0364-3190 (ISSN-L)
  • 1573-6903
DOI
10.1023/a:1022535930009
OpenAlex
W1481406810
Cited by
190
References
7
Citations by year
2025: 3 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 6
FWCI
1.72
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Neurochemical Research (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Myelin Project
  • National Institutes of Health (1r01dk051149-01)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK51149)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD24061, HD-10981, P30HD024061, P01HD010981)
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, ALDP, ABC transporters, peroxisomal membrane proteins, very long chain fatty acids, peroxisome biogenesis, genotype-phenotype correlation, protein dimerization, clinical heterogeneity, neurodegeneration
MeSH terms
Adrenoleukodystrophy, Humans, Genetic Linkage, Mutation, Phenotype, X Chromosome

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