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

DNA polymerase epsilon (Pol epsilon) 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 Pol epsilon, 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 Pol epsilon 1 and also to a lesser extent the Pol epsilon 2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Pol epsilon 1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Pol epsilon catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.