Mutational analysis of patients with X-linked adrenoleukodystrophy
Abstract
Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.
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A mutation hot spot has been identified in exon 5 of ABCD1.
“A mutation hot spot has been identified in exon 5 [Kemp et al., 1994;Kok et al., 1995].”
From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Kok et al., 1995
The exon 5 hot spot mutation involves deletion of two nucleotides (AG) at cDNA position 1415-16, causing a frame shift at Glu471 and a premature stop codon at position 554.
“This mutation involves the deletion of two nucleotides (AG) at cDNA position 1415-16.This results in a frame shift at amino acid residue Glu471 (fs E471) and a premature stop codon at position 554.”
From ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations (2001) · cites this paper as Kok et al., 1995
Cites
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Self-citationA mouse model for X-linked adrenoleukodystrophy
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Investigating ABCD1 mutations in a Taiwanese cohort with hereditary spastic paraplegia phenotype
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- Authors
- Kok, F., Neumann, S., Sarde, C.-O., Zheng, S., Wu, K.-H., Wei, H.-M., Bergin, J., Watkins, P. A., Gould, S., Sack, G., Moser, H., Mandel, J.-L., & Smith, K. D.
- Affiliations
- Kennedy Krieger Institute (US)
- Inserm (FR)
- Corresponding author
- Smith, Kirby D.
- ORCID
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 1995
- Volume
- 6
- Issue
- 2
- Pages
- 104-115
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- OpenAlex
- W2060401928
- Cited by
- 103
- References
- 1
- Citations by year
- 2024: 2 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 3
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Center for Research Resources (RR 000 52, RR 00035)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD24061, P30HD024061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- X-linked adrenoleukodystrophy, ABC transporters, very long chain fatty acids, gene deletion, missense mutations, frameshift mutation, CpG, genotype-phenotype correlation, mutation analysis
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Base Sequence, Chromosome Mapping, DNA Mutational Analysis, Humans, Genetic Linkage, Membrane Proteins, Molecular Sequence Data, Mutation, X Chromosome, Blotting, Southern, ATP-Binding Cassette Transporters, Polymorphism, Single-Stranded Conformational
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