title: Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females.
abstract: In the majority of patients with Pelizaeus-Merzbacher disease, duplication of the proteolipid protein gene PLP1 is responsible, whereas deletion of PLP1 is infrequent. Genomic mechanisms for these submicroscopic chromosomal rearrangements remain unknown. We identified three families with PLP1 deletions (including one family described elsewhere) that arose by three distinct processes. In one family, PLP1 deletion resulted from a maternal balanced submicroscopic insertional translocation of the entire PLP1 gene to the telomere of chromosome 19. PLP1 on the 19qtel is probably inactive by virtue of a position effect, because a healthy male sibling carries the same der(19) chromosome along with a normal X chromosome. Genomic mapping of the deleted segments revealed that the deletions are smaller than most of the PLP1 duplications and involve only two other genes. We hypothesize that the deletion is infrequent, because only the smaller deletions can avoid causing either infertility or lethality. Analyses of the DNA sequence flanking the deletion breakpoints revealed Alu-Alu recombination in the family with translocation. In the other two families, no homologous sequence flanking the breakpoints was found, but the distal breakpoints were embedded in novel low-copy repeats, suggesting the potential involvement of genome architecture in stimulating these rearrangements. In one family, junction sequences revealed a complex recombination event. Our data suggest that PLP1 deletions are likely caused by nonhomologous end joining.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Virginia C
authors.initials: VC
authors.lastname: Thurston
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.forename: Akira
authors.initials: A
authors.lastname: Yoneyama
authors.forename: Lisa
authors.initials: L
authors.lastname: Rosenbarker
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: M E
authors.initials: ME
authors.lastname: Hodes
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D001483:Base Sequence; D002648:Child; D003001:Cloning, Molecular; D004303:Dosage Compensation, Genetic; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D008074:Lipoproteins / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein; D010375:Pedigree; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D010641:Phenotype; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic
chemical_list: D008074:Lipoproteins; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human