title: A rare myelin protein zero (MPZ) variant alters enhancer activity in vitro and in vivo.
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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Dennis
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Burzynski
authors.forename: Jimmy
authors.initials: J
authors.lastname: Huynh
authors.forename: Valerie
authors.initials: V
authors.lastname: Maduro
authors.forename: Chani J
authors.initials: CJ
authors.lastname: Hodonsky
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Khajavi
authors.forename: Kinga
authors.initials: K
authors.lastname: Szigeti
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mukkamala
authors.forename: Seneca L
authors.initials: SL
authors.lastname: Bessling
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
mesh_terms: D000818:Animals; D001665:Binding Sites; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055757:SOXE Transcription Factors / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish
chemical_list: D018993:Myelin P0 Protein; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D014157:Transcription Factors