Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease
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 s...
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Published in | Journal of child neurology Vol. 29; no. 7; p. 924 |
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01.07.2014
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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. |
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AbstractList | 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. |
Author | Šišková, Dana Zámečník, Josef Garbern, Jim Žaliová, Markéta Seeman, Pavel Sakmaryová, Iva Laššuthová, Petra Mazanec, Radim Sixtová, Klára Paděrová, Kateřina Inoue, Ken Haberlová, Jana |
Author_xml | – sequence: 1 givenname: Petra surname: Laššuthová fullname: Laššuthová, Petra email: petra.lassuthova@gmail.com organization: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic petra.lassuthova@gmail.com – sequence: 2 givenname: Markéta surname: Žaliová fullname: Žaliová, Markéta organization: Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 3 givenname: Ken surname: Inoue fullname: Inoue, Ken organization: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan – sequence: 4 givenname: Jana surname: Haberlová fullname: Haberlová, Jana organization: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 5 givenname: Klára surname: Sixtová fullname: Sixtová, Klára organization: Department of Paediatric Neurology, Thomayer's Hospital, Prague, Czech Republic – sequence: 6 givenname: Iva surname: Sakmaryová fullname: Sakmaryová, Iva organization: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 7 givenname: Kateřina surname: Paděrová fullname: Paděrová, Kateřina organization: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 8 givenname: Radim surname: Mazanec fullname: Mazanec, Radim organization: Department of Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 9 givenname: Josef surname: Zámečník fullname: Zámečník, Josef organization: Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic – sequence: 10 givenname: Dana surname: Šišková fullname: Šišková, Dana organization: Department of Paediatric Neurology, Thomayer's Hospital, Prague, Czech Republic – sequence: 11 givenname: Jim surname: Garbern fullname: Garbern, Jim organization: Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA – sequence: 12 givenname: Pavel surname: Seeman fullname: Seeman, Pavel organization: Department of Paediatric Neurology, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Czech Republic |
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Keywords | PLP1 splice-site mutations Pelizaeus-Merzbacher disease |
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Snippet | Pelizaeus-Merzbacher disease is a severe X-linked disorder of central myelination caused by mutations affecting the proteolipid protein gene. We describe 3 new... |
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SubjectTerms | 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 |
Title | Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease |
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