Walne, AJ; Vulliamy, T; Kirwan, M; Plagnol, V; Dokal, I; (2013) Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet , 92 (3) 448 - 453. 10.1016/j.ajhg.2013.02.001.
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Dyskeratosis congenita (DC) and its phenotypically severe variant, Hoyeraal-Hreidarsson syndrome (HHS), are multisystem bone-marrow-failure syndromes in which the principal pathology is defective telomere maintenance. The genetic basis of many cases of DC and HHS remains unknown. Using whole-exome sequencing, we identified biallelic mutations in RTEL1, encoding a helicase essential for telomere maintenance and regulation of homologous recombination, in an individual with familial HHS. Additional screening of RTEL1 identified biallelic mutations in 6/23 index cases with HHS but none in 102 DC or DC-like cases. All 11 mutations in ten HHS individuals from seven families segregated in an autosomal-recessive manner, and telomere lengths were significantly shorter in cases than in controls (p = 0.0003). This group had significantly higher levels of telomeric circles, produced as a consequence of incorrect processing of telomere ends, than did controls (p = 0.0148). These biallelic RTEL1 mutations are responsible for a major subgroup (∼29%) of HHS. Our studies show that cells harboring these mutations have significant defects in telomere maintenance, but not in homologous recombination, and that incorrect resolution of T-loops is a mechanism for telomere shortening and disease causation in humans. They also demonstrate the severe multisystem consequences of its dysfunction.
|Title:||Constitutional mutations in RTEL1 cause severe dyskeratosis congenita.|
|Additional information:||PMCID: PMC3591859|
|Keywords:||Adolescent, Amino Acid Sequence, Child, Child, Preschool, DNA Helicases, Dyskeratosis Congenita, Exome, Female, Fetal Growth Retardation, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Mutation, Sequence Analysis, DNA, Sequence Analysis, Protein, Telomere, Telomere Shortening|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute|
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