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. doi: 10.1084/jem.20121303. Epub 2012 Dec 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alternative Splicing
  • Base Sequence
  • Body Height / genetics
  • Cell Proliferation
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 12 / genetics
  • Consanguinity
  • DNA Mutational Analysis
  • DNA Polymerase II / deficiency
  • DNA Polymerase II / genetics*
  • Facial Bones / abnormalities*
  • Female
  • France
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression
  • Genes, Recessive
  • Growth Disorders / enzymology*
  • Growth Disorders / genetics*
  • Humans
  • Immunologic Deficiency Syndromes / enzymology*
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Introns
  • Livedo Reticularis / enzymology*
  • Livedo Reticularis / genetics*
  • Livedo Reticularis / pathology
  • Male
  • Pedigree
  • Point Mutation
  • Poly-ADP-Ribose Binding Proteins
  • Syndrome
  • Young Adult


  • Poly-ADP-Ribose Binding Proteins
  • DNA Polymerase II
  • POLE protein, human