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Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)
DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and D...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526359/ https://www.ncbi.nlm.nih.gov/pubmed/23230001 http://dx.doi.org/10.1084/jem.20121303 |
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author | Pachlopnik Schmid, Jana Lemoine, Roxane Nehme, Nadine Cormier-Daire, Valéry Revy, Patrick Debeurme, Franck Debré, Marianne Nitschke, Patrick Bole-Feysot, Christine Legeai-Mallet, Laurence Lim, Annick de Villartay, Jean-Pierre Picard, Capucine Durandy, Anne Fischer, Alain de Saint Basile, Geneviève |
author_facet | Pachlopnik Schmid, Jana Lemoine, Roxane Nehme, Nadine Cormier-Daire, Valéry Revy, Patrick Debeurme, Franck Debré, Marianne Nitschke, Patrick Bole-Feysot, Christine Legeai-Mallet, Laurence Lim, Annick de Villartay, Jean-Pierre Picard, Capucine Durandy, Anne Fischer, Alain de Saint Basile, Geneviève |
author_sort | Pachlopnik Schmid, Jana |
collection | PubMed |
description | DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder. |
format | Online Article Text |
id | pubmed-3526359 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-35263592013-06-17 Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) Pachlopnik Schmid, Jana Lemoine, Roxane Nehme, Nadine Cormier-Daire, Valéry Revy, Patrick Debeurme, Franck Debré, Marianne Nitschke, Patrick Bole-Feysot, Christine Legeai-Mallet, Laurence Lim, Annick de Villartay, Jean-Pierre Picard, Capucine Durandy, Anne Fischer, Alain de Saint Basile, Geneviève J Exp Med Brief Definitive Report DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients’ T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder. The Rockefeller University Press 2012-12-17 /pmc/articles/PMC3526359/ /pubmed/23230001 http://dx.doi.org/10.1084/jem.20121303 Text en © 2012 Pachlopnik Schmid et al. https://creativecommons.org/licenses/by-nc-sa/3.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ (https://creativecommons.org/licenses/by-nc-sa/3.0/) ). |
spellingShingle | Brief Definitive Report Pachlopnik Schmid, Jana Lemoine, Roxane Nehme, Nadine Cormier-Daire, Valéry Revy, Patrick Debeurme, Franck Debré, Marianne Nitschke, Patrick Bole-Feysot, Christine Legeai-Mallet, Laurence Lim, Annick de Villartay, Jean-Pierre Picard, Capucine Durandy, Anne Fischer, Alain de Saint Basile, Geneviève Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title | Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title_full | Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title_fullStr | Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title_full_unstemmed | Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title_short | Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”) |
title_sort | polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“fils syndrome”) |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526359/ https://www.ncbi.nlm.nih.gov/pubmed/23230001 http://dx.doi.org/10.1084/jem.20121303 |
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