Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree.

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  • Author(s): Wang Z;Wang Z; Yan A; Lin Y; Xie H; Zhou C; Lan F
  • Source:
    PloS one [PLoS One] 2013; Vol. 8 (3), pp. e57977. Date of Electronic Publication: 2013 Mar 01.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Chromosomes, Human, X* ; Heterozygote* ; Mutation* ; X Chromosome Inactivation*; ATP-Binding Cassette Transporters/*genetics ; Adrenoleukodystrophy/*genetics ; Asian People/*genetics; ATP Binding Cassette Transporter, Subfamily D, Member 1 ; Adrenoleukodystrophy/pathology ; Adult ; Aged ; Alleles ; Base Sequence ; DNA Mutational Analysis ; Female ; Humans ; Molecular Sequence Data ; Pedigree
    • Abstract:
      Background: X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder caused by mutations in the ABCD1 gene. Approximately 20% of X-ALD female carriers may develop neurological symptoms. Skewed X chromosome inactivation (XCI) has been proposed to influence the manifestation of symptoms in X-ALD carriers, but data remain conflicting so far. We identified a three generation kindred, with five heterozygous females, including two manifesting carriers. XCI pattern and the ABCD1 allele expression were assessed in order to determine if symptoms in X-ALD carriers could be related to skewed XCI and whether skewing within this family is more consistent with genetically influenced or completely random XCI.
      Results: We found a high frequency of skewing in this family. Four of five females had skewed XCI, including two manifesting carriers favoring the mutant allele, one asymptomatic carrier favoring the normal allele, and one female who was not an X-ALD carrier. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.
      Conclusions: Our data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms. Furthermore, XCI skewing in this family is genetically influenced. However, the underlying mechanism remains to be substantiated by further experiments.
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    • Accession Number:
      0 (ABCD1 protein, human)
      0 (ATP Binding Cassette Transporter, Subfamily D, Member 1)
      0 (ATP-Binding Cassette Transporters)
    • Publication Date:
      Date Created: 20130308 Date Completed: 20130827 Latest Revision: 20221207
    • Publication Date:
      20231215
    • Accession Number:
      PMC3585930
    • Accession Number:
      10.1371/journal.pone.0057977
    • Accession Number:
      23469258