title: Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease.
abstract: Pelizaeus-Merzbacher disease is a severe X-linked disorder of central myelination caused by mutations affecting the proteolipid protein gene. We describe 3 new PLP1 splicing mutations, their effect on splicing and associated phenotypes. Mutation c.453_453+6del7insA affects the exon 3B donor splice site and disrupts the PLP1-transcript without affecting the DM20, was found in a patient with severe Pelizaeus-Merzbacher disease and in his female cousin with early-onset spastic paraparesis. Mutation c.191+1G>A causes exon 2 skipping with a frame shift, is expected to result in a functionally null allele, and was found in a patient with mild Pelizaeus-Merzbacher disease and in his aunt with late-onset spastic paraparesis. Mutation c.696+1G>A utilizes a cryptic splice site in exon 5, causes partial exon 5 skipping and in-frame deletion, and was found in an isolated patient with a severe classical Pelizaeus-Merzbacher. PLP1 splice-site mutations express a variety of disease phenotypes mediated by different molecular pathogenic mechanisms.
authors.affiliation: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic petra.lassuthova@gmail.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Laššuthová
authors.affiliation: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Žaliová
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Haberlová
authors.affiliation: Department of Paediatric Neurology, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Sixtová
authors.affiliation: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Iva
authors.initials: I
authors.lastname: Sakmaryová
authors.affiliation: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Paděrová
authors.affiliation: Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.affiliation: Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Zámečník
authors.affiliation: Department of Paediatric Neurology, Thomayer's Hospital, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Šišková
authors.affiliation: Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Garbern
authors.affiliation: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
mesh_terms: D001344:Autopsy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D022821:RNA Splice Sites
keywords: PLP1; Pelizaeus-Merzbacher disease; splice-site mutations