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3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations
OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histo...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cambridge University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799666/ http://dx.doi.org/10.1017/cts.2019.235 |
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author | Nair, Divya R Bhoj, Elizabeth |
author_facet | Nair, Divya R Bhoj, Elizabeth |
author_sort | Nair, Divya R |
collection | PubMed |
description | OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histone 3 Family 3 (H3F3) histones (H3.3), encoded by H3F3A and H3F3B, mark active genes, maintain epigenetic memory, and maintain heterochromatin and telomeric integrity. Specific somatic mutations in H3F3A and H3F3B have been strongly associated with pediatric glia and other tumors, but no germline mutations have been reported. The goal of our study was to further understand the functional effects of germline mutations of H3F3A and H3F3B. METHODS/STUDY POPULATION: We analyzed 32 patients bearing de novo germline missense mutations in H3F3A or H3F3B with core phenotypes of progressive neurologic dysfunction and congenital anomalies, but no malignancies. Patient histones were analyzed by quantitative mass spectrometry (qMS). RESULTS/ANTICIPATED RESULTS: qMS results revealed that the mutant histone proteins are present at a concentration similar to that of wild-type H3.3. qMS analysis showed strikingly aberrant PTM patterns that suggested local dysregulation. These patterns are distinct from the dominant negative somatic mutations, which cause more global PTM dysregulation. Patient cells also demonstrated upregulation of the expression of genes related to mitosis and cell division, and had a greater proliferative capacity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggests that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, but may converge on control of cell proliferation. Further clarification of the pathophysiology in these patients can elucidate the roles of histones and histone PTMs in human development and non-syndromic neurodegeneration. In addition, it provides a framework for targeted therapy development for this and related progressive neurologic disorders. |
format | Online Article Text |
id | pubmed-6799666 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cambridge University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-67996662019-10-28 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations Nair, Divya R Bhoj, Elizabeth J Clin Transl Sci Mechanistic Basic to Clinical OBJECTIVES/SPECIFIC AIMS: Histones are nuclear proteins that associate with DNA to facilitate packaging into condensed chromatin. Histones are dynamically decorated with post-translational modifications (PTMs), which regulate such processes as DNA repair, gene expression, mitosis, and meiosis. Histone 3 Family 3 (H3F3) histones (H3.3), encoded by H3F3A and H3F3B, mark active genes, maintain epigenetic memory, and maintain heterochromatin and telomeric integrity. Specific somatic mutations in H3F3A and H3F3B have been strongly associated with pediatric glia and other tumors, but no germline mutations have been reported. The goal of our study was to further understand the functional effects of germline mutations of H3F3A and H3F3B. METHODS/STUDY POPULATION: We analyzed 32 patients bearing de novo germline missense mutations in H3F3A or H3F3B with core phenotypes of progressive neurologic dysfunction and congenital anomalies, but no malignancies. Patient histones were analyzed by quantitative mass spectrometry (qMS). RESULTS/ANTICIPATED RESULTS: qMS results revealed that the mutant histone proteins are present at a concentration similar to that of wild-type H3.3. qMS analysis showed strikingly aberrant PTM patterns that suggested local dysregulation. These patterns are distinct from the dominant negative somatic mutations, which cause more global PTM dysregulation. Patient cells also demonstrated upregulation of the expression of genes related to mitosis and cell division, and had a greater proliferative capacity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our data suggests that the pathogenic mechanism of germline histone mutations is distinct from that of the published cancer-associated somatic histone mutations, but may converge on control of cell proliferation. Further clarification of the pathophysiology in these patients can elucidate the roles of histones and histone PTMs in human development and non-syndromic neurodegeneration. In addition, it provides a framework for targeted therapy development for this and related progressive neurologic disorders. Cambridge University Press 2019-03-27 /pmc/articles/PMC6799666/ http://dx.doi.org/10.1017/cts.2019.235 Text en © The Association for Clinical and Translational Science 2019 http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work. |
spellingShingle | Mechanistic Basic to Clinical Nair, Divya R Bhoj, Elizabeth 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title | 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title_full | 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title_fullStr | 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title_full_unstemmed | 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title_short | 3548 De novo germline variants in Histone 3 Family 3A (H3F3A) and Histone 3 Family 3B (H3F3B) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
title_sort | 3548 de novo germline variants in histone 3 family 3a (h3f3a) and histone 3 family 3b (h3f3b) cause a severe neurodegenerative disorder and functional effects unique from their somatic mutations |
topic | Mechanistic Basic to Clinical |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799666/ http://dx.doi.org/10.1017/cts.2019.235 |
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