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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.

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