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

Hum Mol Genet. 2013 Aug 15;22(16):3239-49. doi: 10.1093/hmg/ddt178. Epub 2013 Apr 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Male
  • Microcephaly / genetics*
  • Microcephaly / metabolism
  • Mutation
  • Sequence Alignment
  • Sequence Analysis, RNA
  • Telomerase / genetics
  • Telomerase / metabolism
  • Telomere / metabolism*
  • Telomere / ultrastructure
  • Telomere Homeostasis / genetics*
  • Telomere Shortening*

Substances

  • Telomerase
  • RTEL1 protein, human
  • DNA Helicases

Supplementary concepts

  • Hoyeraal Hreidarsson syndrome