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

PLoS One. 2013;8(3):e57977. doi: 10.1371/journal.pone.0057977. Epub 2013 Mar 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters / genetics*
  • Adrenoleukodystrophy / genetics*
  • Adrenoleukodystrophy / pathology
  • Adult
  • Aged
  • Alleles
  • Asian People / genetics*
  • Base Sequence
  • Chromosomes, Human, X*
  • DNA Mutational Analysis
  • Female
  • Heterozygote*
  • Humans
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • X Chromosome Inactivation*

Substances

  • ABCD1 protein, human
  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters

Grants and funding

This work was supported by the National Science Foundation for Young Scientists of China (Grant No. 31200932) and the Natural Science Foundation of Fujian Province, China (No. 2012J05158). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.