title: Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.
abstract: The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA. mhodes@iupui.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Hodes
authors.forename: K
authors.initials: K
authors.lastname: Woodward
authors.forename: N B
authors.initials: NB
authors.lastname: Spinner
authors.forename: B S
authors.initials: BS
authors.lastname: Emanuel
authors.forename: A
authors.initials: A
authors.lastname: Enrico-Simon
authors.forename: J
authors.initials: J
authors.lastname: Kamholz
authors.forename: D
authors.initials: D
authors.lastname: Stambolian
authors.forename: E H
authors.initials: EH
authors.lastname: Zackai
authors.forename: V M
authors.initials: VM
authors.lastname: Pratt
authors.forename: I T
authors.initials: IT
authors.lastname: Thomas
authors.forename: K
authors.initials: K
authors.lastname: Crandall
authors.forename: S R
authors.initials: SR
authors.lastname: Dlouhy
authors.forename: S
authors.initials: S
authors.lastname: Malcolm
mesh_terms: D002648:Child; D002675:Child, Preschool; D007446:Chromosome Inversion; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D020732:Cytogenetic Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D020131:Genes, Duplicate / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D016254:Mutagenesis, Insertional / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D010375:Pedigree; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011995:Recombination, Genetic / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*
chemical_list: D018991:Myelin Proteolipid Protein