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A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels
Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gl...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691473/ https://www.ncbi.nlm.nih.gov/pubmed/37890975 http://dx.doi.org/10.1101/gad.350733.123 |
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author | Zhou, Jian Cattoglio, Claudia Shao, Yingyao Tirumala, Harini P. Vetralla, Carlo Bajikar, Sameer S. Li, Yan Chen, Hu Wang, Qi Wu, Zhenyu Tang, Bing Zahabiyon, Mahla Bajic, Aleksandar Meng, Xiangling Ferrie, Jack J. LaGrone, Anel Zhang, Ping Kim, Jean J. Tang, Jianrong Liu, Zhandong Darzacq, Xavier Heintz, Nathaniel Tjian, Robert Zoghbi, Huda Y. |
author_facet | Zhou, Jian Cattoglio, Claudia Shao, Yingyao Tirumala, Harini P. Vetralla, Carlo Bajikar, Sameer S. Li, Yan Chen, Hu Wang, Qi Wu, Zhenyu Tang, Bing Zahabiyon, Mahla Bajic, Aleksandar Meng, Xiangling Ferrie, Jack J. LaGrone, Anel Zhang, Ping Kim, Jean J. Tang, Jianrong Liu, Zhandong Darzacq, Xavier Heintz, Nathaniel Tjian, Robert Zoghbi, Huda Y. |
author_sort | Zhou, Jian |
collection | PubMed |
description | Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases. |
format | Online Article Text |
id | pubmed-10691473 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-106914732023-12-02 A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels Zhou, Jian Cattoglio, Claudia Shao, Yingyao Tirumala, Harini P. Vetralla, Carlo Bajikar, Sameer S. Li, Yan Chen, Hu Wang, Qi Wu, Zhenyu Tang, Bing Zahabiyon, Mahla Bajic, Aleksandar Meng, Xiangling Ferrie, Jack J. LaGrone, Anel Zhang, Ping Kim, Jean J. Tang, Jianrong Liu, Zhandong Darzacq, Xavier Heintz, Nathaniel Tjian, Robert Zoghbi, Huda Y. Genes Dev Research Papers Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases. Cold Spring Harbor Laboratory Press 2023-10-01 /pmc/articles/PMC10691473/ /pubmed/37890975 http://dx.doi.org/10.1101/gad.350733.123 Text en © 2023 Zhou et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by/4.0/This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Papers Zhou, Jian Cattoglio, Claudia Shao, Yingyao Tirumala, Harini P. Vetralla, Carlo Bajikar, Sameer S. Li, Yan Chen, Hu Wang, Qi Wu, Zhenyu Tang, Bing Zahabiyon, Mahla Bajic, Aleksandar Meng, Xiangling Ferrie, Jack J. LaGrone, Anel Zhang, Ping Kim, Jean J. Tang, Jianrong Liu, Zhandong Darzacq, Xavier Heintz, Nathaniel Tjian, Robert Zoghbi, Huda Y. A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title | A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title_full | A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title_fullStr | A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title_full_unstemmed | A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title_short | A novel pathogenic mutation of MeCP2 impairs chromatin association independent of protein levels |
title_sort | novel pathogenic mutation of mecp2 impairs chromatin association independent of protein levels |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691473/ https://www.ncbi.nlm.nih.gov/pubmed/37890975 http://dx.doi.org/10.1101/gad.350733.123 |
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