Abstract
BackgroundMyelin 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.MethodologyWe 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 FindingsOur 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.ConclusionsThis 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.
Highlights
Myelin protein zero (MPZ) is an integral membrane glycoprotein and a major structural component of peripheral nervous system myelin
The identification of null MPZ alleles in patients with cause demyelinatingCharcot-Marie-Tooth disease type 1B (CMT1B) suggests that there is a threshold in the amount of MPZ required for proper myelination [8]; in support of this notion, mice that are heterozygous for an Mpz-knockout allele develop a late-onset peripheral demyelinating neuropathy [9]
We report a rare human variant that alters the activity of an MPZ enhancer, a finding that has implications for understanding the transcriptional regulation of MPZ and for assessing the functional significance of non-coding variants within genes implicated in human inherited neuropathies
Summary
Myelin protein zero (MPZ) is an integral membrane glycoprotein and a major structural component of peripheral nervous system myelin. Other studies have demonstrated that SOX10 and EGR2 bind to the intronic enhancer both in vitro and in vivo, and that mutagenesis of the SOX10-binding sites within this enhancer reduces binding of these transcription factors [11,14,15,16,17] Such findings suggest that variants within these SOX10- and EGR2-binding sites may affect MPZ transcriptional regulation. In support of this notion, a CMT-associated mutation has been identified in a SOX10 binding site at the gap junction protein beta 1 (GJB1) locus [18,19]. 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
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