Polymerase epsilon1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").
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Pachlopnik Schmid J, Lemoine R, Nehme N, Cormier-Daire V, Revy P, Debeurme F, Debre M, Nitschke P, Bole-Feysot C, Legeai-Mallet L, Lim A, de Villartay JP, Picard C, Durandy A, Fischer A, de Saint Basile G
Polymerase epsilon1 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. doi: 10.1084/jem.20121303. Epub 2012 Dec 10.
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- 23230001 [ View in PubMed]
- Abstract
DNA polymerase epsilon (Polepsilon) 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 epsilon 1), encoding the catalytic subunit of Polepsilon, 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 Polepsilon1 and also to a lesser extent the Polepsilon2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polepsilon1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polepsilon catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.