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Rockefeller University Press, Journal of Experimental Medicine, 13(209), p. 2323-2330, 2012

DOI: 10.1084/jem.20121303

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Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”)

Journal article published in 2012 by Jana Pachlopnik Schmid ORCID, Jana Pachlopnik Schmid, Roxane Lemoine, Nadine Nehme, Valéry Cormier-Daire ORCID, Patrick Revy, Franck Debeurme, Jean-Pierre de Villartay, Marianne Debré, Patrick Nitschke, Christine Bole-Feysot, Laurence Legeai-Mallet, Annick Lim, de Villartay Jp, Capucine Picard ORCID and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.