title: PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1.
abstract: The proteolipid protein 1 (PLP1) gene is known to be mutated in the X-linked disorders of myelin formation Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2. The most commonly found PLP1 mutations are gene duplications (60-70%) and point mutations (20%). About 20% of patients with a PMD phenotype do not present identified PLP1 mutation, thus suggesting genetic heterogeneity and/or undetected PLP1 abnormalities. Except the recently described MLPA screening the seven exonic regions, the currently used techniques to quantify PLP1 gene copy number do not investigate small intragenic PLP1 rearrangements. Using the multiplex amplifiable probe hybridization (MAPH) technique, we looked simultaneously for intragenic rearrangements along the PLP1 gene (exonic and regulatory regions) and for rearrangements in the GPM6B candidate gene (a member of the proteolipid protein family). We tested 262 hypomyelinating patients: 56 PLP1 duplicated patients, 1 PLP1 triplicated patient, and 205 patients presenting a leukodystrophy of undetermined origin with brain MRI suggesting a defect in myelin formation. Our results show that MAPH is an alternative reliable technique for diagnosis of PLP1 gene copy number. It allows us (1) to demonstrate that all PLP1 duplications previously found encompass the whole gene, (2) to establish that copy number changes in GPM6B and intragenic duplications of PLP1 are very unlikely to be involved in the etiology of UHL, and (3) to identify one partial triplication and two partial deletions of PLP1 in patients presenting with a PMD phenotype.
authors.affiliation: INSERM U 384, Faculté de Médecine, Place Henri Dunant, 63000 Clermont-Ferrand, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Combes
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Bonnet-Dupeyron
authors.forename: Fernande
authors.initials: F
authors.lastname: Gauthier-Barichard
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: John A L
authors.initials: JA
authors.lastname: Armour
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.forename: Catherine
authors.initials: C
authors.lastname: Vaurs-Barrière
mesh_terms: D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015321:Gene Rearrangement; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization / Q000379:methods*; D015203:Reproducibility of Results
chemical_list: C484160:GPM6B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C472930:PLP1 protein, human