PUBLICATION

A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo

Authors
Antonellis, A., Dennis, M.Y., Burzynski, G., Huynh, J., Maduro, V., Hodonsky, C.J., Khajavi, M., Szigeti, K., Mukkamala, S., Bessling, S.L.; NISC Comparative Sequencing Program, Pavan, W.J., McCallion, A.S., Lupski, J.R., and Green, E.D.
ID
ZDB-PUB-110103-11
Date
2010
Source
PLoS One   5(12): e14346 (Journal)
Registered Authors
McCallion, Andy
Keywords
none
MeSH Terms
  • Animals
  • Binding Sites
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation
  • Genetic Variation
  • Humans
  • In Vitro Techniques
  • Mice
  • Mutation
  • Myelin P0 Protein/genetics*
  • Myelin P0 Protein/metabolism
  • Rats
  • SOXE Transcription Factors/metabolism
  • Sequence Analysis, DNA
  • Species Specificity
  • Transcription Factors/metabolism
  • Zebrafish
PubMed
21179557 Full text @ PLoS One
Abstract
BACKGROUND: Myelin protein zero (MPZ) is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants) that affect MPZ expression. METHODOLOGY: We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants. PRINCIPAL FINDINGS: Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish. CONCLUSIONS: This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping