Three New PLP1 Splicing Mutations Demonstrate Pathogenic and Phenotypic Diversity of Pelizaeus-Merzbacher Disease. (July 2014)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of child neurology. Volume 29:Number 7(2014:Jul.)
• Page Start: 924
• Page End: 931
• Publication Date: 2014-07
• Subjects: Pelizaeus-Merzbacher disease -- PLP1 -- splice-site mutations; Nervous system -- Diseases -- Periodicals; 618.928
• DOI: 10.1177/0883073813492387
• Languages: English
• ISSNs: 0883-0738

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.