Three New PLP1 Splicing Mutations Demonstrate Pathogenic and Phenotypic Diversity of Pelizaeus-Merzbacher Disease

• Published in: Journal of child neurology 2014-07, Vol.29 (7), p.924-931
• Main Authors: Laššuthová, Petra, Žaliová, Markéta, Inoue, Ken, Haberlová, Jana, Sixtová, Klára, Sakmaryová, Iva, Paděrová, Kateřina, Mazanec, Radim, Zámečník, Josef, Šišková, Dana, Garbern, Jim, Seeman, Pavel
• Format: Article
• Language: English
• Subjects: Autopsy; Child; Child, Preschool; DNA Mutational Analysis; Family Health; Female; Humans; Male; Middle Aged; Mutation - genetics; Myelin Proteolipid Protein - genetics; Neural Conduction - genetics; Pelizaeus-Merzbacher Disease - genetics; Pelizaeus-Merzbacher Disease - pathology; Pelizaeus-Merzbacher Disease - physiopathology; Phenotype; RNA Splice Sites - genetics
• ISSN: 0883-0738; 1708-8283
• DOI: 10.1177/0883073813492387

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.