title: X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations.
abstract: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disease caused by coding sequence mutations in the PLP gene, sub-microscopic duplications of variable sizes including the PLP gene or very rarely deletions of the PLP gene. We analysed the X inactivation pattern in blood of PMD female carriers with duplications and with point mutations. In the majority of duplication carriers (7/11), the X chromosome bearing the duplication was preferentially inactivated, whereas a random pattern of X inactivation was detected in point mutation carriers (3/3), a deletion carrier (1/1), affected females (4/4) who did not have a recognised mutation and normal control females. However 2/5 non-carrier female relatives of patients with a duplication, had skewed X inactivation. The skewed pattern of inactivation observed in most duplication carriers and not in mutation carriers suggests a) that there is selection against those cells in which the duplicated X chromosome is active and b) other expressed sequences within the duplicated region rather than mutant PLP may be responsible. Since the skewed X inactivation did not segregate with the disease in two families and the pattern of X inactivation was variable among the duplication carriers, the pattern X inactivation is an unsuitable diagnostic tool for female carriers of PMD.
authors.affiliation: Molecular Genetics Unit, Institute of Child Health, London, UK. kwoodwar@hgmp.mrc.ac.uk
authors.forename: K
authors.initials: K
authors.lastname: Woodward
authors.forename: K
authors.initials: K
authors.lastname: Kirtland
authors.forename: S
authors.initials: S
authors.lastname: Dlouhy
authors.forename: W
authors.initials: W
authors.lastname: Raskind
authors.forename: T
authors.initials: T
authors.lastname: Bird
authors.forename: S
authors.initials: S
authors.lastname: Malcolm
authors.forename: D
authors.initials: D
authors.lastname: Abeliovich
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D010641:Phenotype; D020161:Physical Chromosome Mapping; D017354:Point Mutation; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C078341:MYT1 protein, human; D014157:Transcription Factors