Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus-Merzbacher disease patient with a partial PLP1 duplication

J Hum Genet. 2012 Sep;57(9):580-6. doi: 10.1038/jhg.2012.71. Epub 2012 Jun 14.

Abstract

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder characterized by dysmyelination of the central nervous system (CNS). We identified a rare partial duplication of the proteolipid protein 1 gene (PLP1) in a patient with PMD. To assess the underlying effect of this duplication, we examined PLP1 expression in induced pluripotent stem (iPS) cells generated from the patient's fibroblasts. Disease-specific iPS cells were generated from skin fibroblasts obtained from the indicated PMD patient and two other PMD patients having a 637-kb chromosomal duplication including entire PLP1 and a novel missense mutation (W212C) of PLP1, by transfections of OCT3/4, C-MYC, KLF4 and SOX2 using retro-virus vectors. PLP1 expressions in the generated iPS cells were examined by northern blot analysis. Although PLP1 expression was confirmed in iPS cells generated from two patients with the entire PLP1 duplication and the missense mutation of PLP1, iPS cells generated from the patient with the partial PLP1 duplication manifesting a milder form of PMD showed null expression. This indicated that the underlying effect of the partial PLP1 duplication identified in this study was different from other PLP1 alterations including a typical duplication and a missense mutation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Base Sequence
  • Brain / pathology
  • Cell Line, Tumor
  • Child, Preschool
  • Chromosome Breakpoints
  • Female
  • Gene Duplication*
  • Gene Expression Regulation*
  • Genotype
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Kruppel-Like Factor 4
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Myelin Proteolipid Protein / genetics*
  • Myelin Proteolipid Protein / metabolism
  • Pelizaeus-Merzbacher Disease / diagnosis
  • Pelizaeus-Merzbacher Disease / genetics*
  • Pelizaeus-Merzbacher Disease / metabolism

Substances

  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Myelin Proteolipid Protein
  • PLP1 protein, human