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Cited by 32Metabolism and Genetic DisordersLysosomal Storage Disorders ResearchGenetics and Neurodevelopmental Disorders

Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms

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Salsano, Ettore, Tabano, Silvia, Sirchia, Silvia M, Colapietro, Patrizia, Castellotti, Barbara, Gellera, Cinzia, Rimoldi, Marco, Pensato, Viviana +4 more·2012·Orphanet Journal of Rare Diseases
DOI 10.1186/1750-1172-7-10PMC PMC3298485
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Abstract

BACKGROUND: Approximately 20% of adrenoleukodystrophy (X-ALD) female carriers may develop clinical manifestations, typically consisting of progressive spastic gait, sensory deficits and bladder dysfunctions. A skewing in X Chromosome Inactivation (XCI), leading to the preferential expression of the X chromosome carrying the mutant ABCD1 allele, has been proposed as a mechanism influencing X-linked adrenoleukodystrophy (X-ALD) carrier phenotype, but reported data so far are conflicting. METHODS: To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify ABCD1 allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients. RESULTS: We found severely (≥90:10) or moderately (≥75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant ABCD1 allele, irrespective of the manifestation of symptoms. The expression of mutant ABCD1 allele also correlates with plasma VLCFA concentrations. CONCLUSIONS: Our results indicate that preferential XCI leads to the favored expression of the mutant ABCD1 allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant ABCD1 allele, but argue against the use of XCI pattern, ABCD1 allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.

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  • Slowly progressive AMN symptoms occur in approximately 65% of heterozygous women by age 60 due to inactivation of the non-mutated X chromosome and mosaic expression of X-linked genes in neural cells.

    “Although ALD is an X-linked disease, slowly progressive AMN symptoms occur in ~65% of heterozygous women by the age of 60 years [31,47,59,60] due to the inactivation of the non-mutated X chromosome and the mosaic expression of X-linked genes in neural cells [60,61,62,63].”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [63]

    The Background (page unavailable) describes progressive AMN-like symptoms in female X-ALD carriers and explains that X-inactivation makes females mosaic for X-linked gene expression. But it estimates symptoms in about 20% of carriers, not 65% by age 60. The Discussion (page unavailable) reports no significant association between symptoms and X-inactivation patterns in blood; it says X-inactivation in carriers’ brains was not investigated, so it does not establish the claimed cause in neural cells. (LLM, conf=0.88)

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Cited by

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Authors
Salsano, E., Tabano, S., Sirchia, S. M., Colapietro, P., Castellotti, B., Gellera, C., Rimoldi, M., Pensato, V., Mariotti, C., Pareyson, D., Miozzo, M., & Uziel, G.
Affiliations
  • University of Milan (IT)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
Corresponding author
Miozzo, Monica
ORCID
Venue
Orphanet Journal of Rare Diseases
Publisher
Springer Science and Business Media LLC
Published
2012-01-26
Volume
7
Issue
1
Pages
10-10
ISSN
1750-1172 (ISSN-L)
DOI
10.1186/1750-1172-7-10
PMC
PMC3298485
OpenAlex
W2096830747
Cited by
32
References
2
Citations by year
2025: 3 · 2024: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2018: 4 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 4
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (241622)
  • FP7 Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
adrenoleukodystrophy, X-linked adrenoleukodystrophy, female carriers, X-chromosome inactivation skewing, very long chain fatty acids, pyrosequencing, biomarkers, peripheral blood mononuclear cells
MeSH terms
ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Adult, Aged, Alleles, Female, Gene Expression Regulation, Humans, Middle Aged, Mutation, ATP-Binding Cassette Transporters, Chromosomes, Human, X, Young Adult

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