title: Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA.
abstract: We describe a 28-year-old male patient with a mild course of Pelizaeus-Merzbacher disease (PMD) who presented with developmental delay in his second year of life and was able to walk until 12 years of age. Several computed tomography scans in infancy and youth were normal, the diagnosis of PMD was eventually suggested by magnetic resonance imaging at the age of 24 years. Analysis of the proteolipid protein gene (PLP1) revealed a nucleotide exchange (c.762G>T) at the 3' border of exon 6, which did not entail an amino acid exchange but adversely affected splicing. PCR analysis of fibroblast cDNA showed that c.762G>T resulted in partial skipping of exon 6 in the PLP1 mRNA. Exclusion of exon 6 does not alter the reading frame but leads to absence of amino acids 232-253 that constitute a main part of the fourth transmembrane helix of the PLP protein. Remarkably, residual wild-type splicing was also detected in the patient's cultured fibroblasts. This might explain the mild phenotype in this case, as exon 6 skipping mutations resulted in a severe course of disease in other patients.
authors.affiliation: Institute for Human Genetics, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Hübner
authors.forename: A
authors.initials: A
authors.lastname: Senning
authors.forename: U
authors.initials: U
authors.lastname: Orth
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.forename: H
authors.initials: H
authors.lastname: Urbach
authors.forename: A
authors.initials: A
authors.lastname: Gal
authors.forename: S
authors.initials: S
authors.lastname: Rudnik-Schöneborn
mesh_terms: D000328:Adult; D015152:Blotting, Northern / Q000379:methods; D015139:Blotting, Southern / Q000379:methods; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D062792:MARVEL Domain-Containing Proteins; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008958:Models, Molecular; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D011510:Proteolipids; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D062792:MARVEL Domain-Containing Proteins; D008565:Membrane Proteins; C094765:PLP2 protein, human; D011510:Proteolipids; D012333:RNA, Messenger