Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability

• Published in: Human molecular genetics Vol. 22; no. 16; pp. 3239 - 3249
• Main Authors: Le Guen, Tangui, Jullien, Laurent, Touzot, Fabien, Schertzer, Michael, Gaillard, Laetitia, Perderiset, Mylène, Carpentier, Wassila, Nitschke, Patrick, Picard, Capucine, Couillault, Gérard, Soulier, Jean, Fischer, Alain, Callebaut, Isabelle, Jabado, Nada, Londono-Vallejo, Arturo, de Villartay, Jean-Pierre, Revy, Patrick
• Format: Journal Article
• Language: English
• Published: England Oxford University Press (OUP) 15.08.2013
• Subjects: Biochemistry, Molecular Biology; Cells, Cultured; Child, Preschool; DNA Damage; DNA Helicases - chemistry; DNA Helicases - deficiency; DNA Helicases - genetics; DNA Helicases - metabolism; DNA Replication; Dyskeratosis Congenita - genetics; Dyskeratosis Congenita - metabolism; Exome; Female; Fetal Growth Retardation - genetics; Fetal Growth Retardation - metabolism; Genetic Linkage; Genomic Instability; Humans; Infant; Intellectual Disability - genetics; Intellectual Disability - metabolism; Life Sciences; Male; Microcephaly - genetics; Microcephaly - metabolism; Mutation; Sequence Alignment; Sequence Analysis, RNA; Telomerase - genetics; Telomerase - metabolism; Telomere - metabolism; Telomere - ultrastructure; Telomere Homeostasis - genetics; Telomere Shortening
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt178

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.