title: Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").
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.
authors.affiliation: National Institute of Health and Medical Research (INSERM) Unit 768, Paris, France.
authors.forename: Jana
authors.initials: J
authors.lastname: Pachlopnik Schmid
authors.forename: Roxane
authors.initials: R
authors.lastname: Lemoine
authors.forename: Nadine
authors.initials: N
authors.lastname: Nehme
authors.forename: Valéry
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Franck
authors.initials: F
authors.lastname: Debeurme
authors.forename: Marianne
authors.initials: M
authors.lastname: Debré
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D001827:Body Height / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004257:DNA Polymerase II / Q000172:deficiency / Q000235:genetics*; D005147:Facial Bones / Q000002:abnormalities*; D005260:Female; D005602:France; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D015870:Gene Expression; D005808:Genes, Recessive; D006130:Growth Disorders / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D007438:Introns; D054068:Livedo Reticularis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D013577:Syndrome; D055815:Young Adult
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human