title: Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.
abstract: Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrow failure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomere dysfunction and these diseases. By combining whole-genome linkage analysis and exome sequencing, we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.
authors.affiliation: INSERM U768, Paris, France.
authors.forename: Tangui
authors.initials: T
authors.lastname: Le Guen
authors.forename: Laurent
authors.initials: L
authors.lastname: Jullien
authors.forename: Fabien
authors.initials: F
authors.lastname: Touzot
authors.forename: Michael
authors.initials: M
authors.lastname: Schertzer
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gaillard
authors.forename: Mylène
authors.initials: M
authors.lastname: Perderiset
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Gérard
authors.initials: G
authors.lastname: Couillault
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Arturo
authors.initials: A
authors.lastname: Londono-Vallejo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
mesh_terms: D002478:Cells, Cultured; D002675:Child, Preschool; D004249:DNA Damage; D004265:DNA Helicases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D008040:Genetic Linkage; D042822:Genomic Instability; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism* / Q000648:ultrastructure; D059505:Telomere Homeostasis / Q000235:genetics*; D059506:Telomere Shortening
chemical_list: D019098:Telomerase; C532890:RTEL1 protein, human; D004265:DNA Helicases