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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
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.
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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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