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.

Department of Mental Retardation and Birth Defect Research National Institute of Neuroscience National Center of Neurology and Psychiatry Tokyo Japan

Department of Neurology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Czech Republic

Department of Neurology and Center for Molecular Medicine and Genetics Wayne State University School of Medicine Detroit MI USA

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Czech Republic

Department of Paediatric Neurology 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Czech Republic

Department of Paediatric Neurology Thomayer's Hospital Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Czech Republic

Citace poskytuje Crossref.org

PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing