A rare myelin protein zero (MPZ) variant alters enhancer activity in Vitro and in Vivo

Anthony Antonellis, Megan Dennis, Grzegorz Burzynski, Jimmy Huynh, Valerie Maduro, Chani J. Hodonsky, Mehrdad Khajavi, Kinga Szigeti, Sandeep Mukkamala, Seneca L. Bessling, William J. Pavan, Andrew S. McCallion, James R. Lupski, Eric D. Green

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Article numbere14346
JournalPLoS One
Issue number12
StatePublished - Dec 1 2010
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)


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