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Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").
J Exp Med. 2012 Dec 17; 209(13):2323-30.JE

Abstract

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.

Authors+Show Affiliations

National Institute of Health and Medical Research (INSERM) Unit 768, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23230001

Citation

Pachlopnik Schmid, Jana, et al. "Polymerase Ε1 Mutation in a Human Syndrome With Facial Dysmorphism, Immunodeficiency, Livedo, and Short Stature ("FILS Syndrome")." The Journal of Experimental Medicine, vol. 209, no. 13, 2012, pp. 2323-30.
Pachlopnik Schmid J, Lemoine R, Nehme N, et al. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). J Exp Med. 2012;209(13):2323-30.
Pachlopnik Schmid, J., Lemoine, R., Nehme, N., Cormier-Daire, V., Revy, P., Debeurme, F., Debré, M., Nitschke, P., Bole-Feysot, C., Legeai-Mallet, L., Lim, A., de Villartay, J. P., Picard, C., Durandy, A., Fischer, A., & de Saint Basile, G. (2012). Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). The Journal of Experimental Medicine, 209(13), 2323-30. https://doi.org/10.1084/jem.20121303
Pachlopnik Schmid J, et al. Polymerase Ε1 Mutation in a Human Syndrome With Facial Dysmorphism, Immunodeficiency, Livedo, and Short Stature ("FILS Syndrome"). J Exp Med. 2012 Dec 17;209(13):2323-30. PubMed PMID: 23230001.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). AU - Pachlopnik Schmid,Jana, AU - Lemoine,Roxane, AU - Nehme,Nadine, AU - Cormier-Daire,Valéry, AU - Revy,Patrick, AU - Debeurme,Franck, AU - Debré,Marianne, AU - Nitschke,Patrick, AU - Bole-Feysot,Christine, AU - Legeai-Mallet,Laurence, AU - Lim,Annick, AU - de Villartay,Jean-Pierre, AU - Picard,Capucine, AU - Durandy,Anne, AU - Fischer,Alain, AU - de Saint Basile,Geneviève, Y1 - 2012/12/10/ PY - 2012/12/12/entrez PY - 2012/12/12/pubmed PY - 2013/2/26/medline SP - 2323 EP - 30 JF - The Journal of experimental medicine JO - J Exp Med VL - 209 IS - 13 N2 - 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. SN - 1540-9538 UR - https://www.unboundmedicine.com/medline/citation/23230001/Polymerase_ε1_mutation_in_a_human_syndrome_with_facial_dysmorphism_immunodeficiency_livedo_and_short_stature__"FILS_syndrome"__ L2 - https://rupress.org/jem/article-lookup/doi/10.1084/jem.20121303 DB - PRIME DP - Unbound Medicine ER -