title: Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease.
abstract: Pelizaeus-Merzbacher disease (PMD) is a rare X-chromosomal neurodegenerative disorder that affects primarily the white matter of the central nervous system and is caused by mutations of the PLP1 (proteolipid protein 1) gene. We performed mutation analysis of 133 male patients with suspected PMD. Following SSCP analysis of all coding exons of PLP1, we found most likely pathogenic mutations (single base substitutions and small rearrangements) including 17 novel sequence variants in 21 (15.8%) patients. Most patients with missense mutations had a severe phenotype. Twelve patients (9.0%) carried a duplication of the entire gene, as demonstrated by quantitative real-time PCR, and presented with a variable clinical phenotype including mild, classical, and severe courses of disease. Two patients had large deletions, spanning approximately 115 kb, that included the PLP1 gene. In total, we identified pathogenic mutations involving PLP1 in 35 (26.3%) of the 133 patients analyzed.
authors.affiliation: Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Orth
authors.forename: Arne
authors.initials: A
authors.lastname: Senning
authors.forename: Cordula
authors.initials: C
authors.lastname: Steglich
authors.forename: Alfried
authors.initials: A
authors.lastname: Kohlschütter
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
mesh_terms: D019943:Amino Acid Substitution; D018389:Codon, Nonsense; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion; D012720:Severity of Illness Index; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D022821:RNA Splice Sites; C489803:RAB9B protein, human; D020691:rab GTP-Binding Proteins