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A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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, sugge...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002941/ https://www.ncbi.nlm.nih.gov/pubmed/21179557 http://dx.doi.org/10.1371/journal.pone.0014346 |
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author | Antonellis, Anthony Dennis, Megan Y. Burzynski, Grzegorz Huynh, Jimmy Maduro, Valerie Hodonsky, Chani J. Khajavi, Mehrdad Szigeti, Kinga Mukkamala, Sandeep Bessling, Seneca L. Pavan, William J. McCallion, Andrew S. Lupski, James R. Green, Eric D. |
author_facet | Antonellis, Anthony Dennis, Megan Y. Burzynski, Grzegorz Huynh, Jimmy Maduro, Valerie Hodonsky, Chani J. Khajavi, Mehrdad Szigeti, Kinga Mukkamala, Sandeep Bessling, Seneca L. Pavan, William J. McCallion, Andrew S. Lupski, James R. Green, Eric D. |
author_sort | Antonellis, Anthony |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-3002941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30029412010-12-21 A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo Antonellis, Anthony Dennis, Megan Y. Burzynski, Grzegorz Huynh, Jimmy Maduro, Valerie Hodonsky, Chani J. Khajavi, Mehrdad Szigeti, Kinga Mukkamala, Sandeep Bessling, Seneca L. Pavan, William J. McCallion, Andrew S. Lupski, James R. Green, Eric D. PLoS One Research Article 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. Public Library of Science 2010-12-16 /pmc/articles/PMC3002941/ /pubmed/21179557 http://dx.doi.org/10.1371/journal.pone.0014346 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Antonellis, Anthony Dennis, Megan Y. Burzynski, Grzegorz Huynh, Jimmy Maduro, Valerie Hodonsky, Chani J. Khajavi, Mehrdad Szigeti, Kinga Mukkamala, Sandeep Bessling, Seneca L. Pavan, William J. McCallion, Andrew S. Lupski, James R. Green, Eric D. A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo |
title | A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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title_full | A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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title_fullStr | A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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title_full_unstemmed | A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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title_short | A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
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title_sort | rare myelin protein zero (mpz) variant alters enhancer activity in vitro and in vivo |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002941/ https://www.ncbi.nlm.nih.gov/pubmed/21179557 http://dx.doi.org/10.1371/journal.pone.0014346 |
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