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

Author:

Pachlopnik Schmid Jana112,Lemoine Roxane12,Nehme Nadine12,Cormier-Daire Valéry12,Revy Patrick12,Debeurme Franck12,Debré Marianne1,Nitschke Patrick2,Bole-Feysot Christine2,Legeai-Mallet Laurence12,Lim Annick3,de Villartay Jean-Pierre112,Picard Capucine112,Durandy Anne1112,Fischer Alain112,de Saint Basile Geneviève1112

Affiliation:

1. National Institute of Health and Medical Research (INSERM) Unit 768; Pediatric Hematology-Immunology-Rheumatology Unit, AP-HP; Department of Genetics, INSERM Unit 781; Laboratory of Human Genetics of Infectious Disease, INSERM Unit 980; and Study Center for Primary Immunodeficiencies, AP-HP; Necker Hospital for Sick Children, 75015 Paris, France

2. Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France

3. Department of Immunology, Pasteur Institute, 75724 Paris, France

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Reference15 articles.

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