title: Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese 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.
authors.affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Fuzhou General Hospital, Fuzhou, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.forename: Aizhen
authors.initials: A
authors.lastname: Yan
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Lin
authors.forename: Haihua
authors.initials: H
authors.lastname: Xie
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhou
authors.forename: Fenghua
authors.initials: F
authors.lastname: Lan
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D049951:X Chromosome Inactivation
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters