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Hum Mutat. 2016 May;37(5):469-72. doi: 10.1002/humu.22966. Epub 2016 Feb 23.

Mutations of the RTEL1 Helicase in a Hoyeraal-Hreidarsson Syndrome Patient Highlight the Importance of the ARCH Domain.

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INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Labellisé Ligue.
Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Assistance Publique des Hôpitaux de Paris, Hôpital Bichat, Service de Génétique, Université Paris Diderot, Paris, France.
Department of Genetics, INSERM UMR 1163, Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Necker enfants malades Hospital, Paris, France.
Assistance Publique - Hôpitaux de Paris, Hôpital Robert-Debré, Service d'Hématologie Pédiatrique, Paris, France.
Institute of Hematology (IUH), INSERM UMR944/CNRS UMR7212, Saint-Louis Hospital and University Paris Diderot, Sorbonne Paris Cité, av Claude, Vellefaux, Paris, France.
Telomeres and Cancer Laboratory, Labellisé Ligue, Department UMR3244, Institut Curie, Paris, France.
IMPMC, Sorbonne Universités, UMR CNRS 7590, UPMC Univ Paris06, Muséum National d'Histoire Naturelle, IRD UMR 206, Paris, France.


The DNA helicase RTEL1 participates in telomere maintenance and genome stability. Biallelic mutations in the RTEL1 gene account for the severe telomere biology disorder characteristic of the Hoyeraal-Hreidarsson syndrome (HH). Here, we report a HH patient (P4) carrying two novel compound heterozygous mutations in RTEL1: a premature stop codon (c.949A>T, p.Lys317*) and an intronic deletion leading to an exon skipping and an in-frame deletion of 25 amino-acids (p.Ile398_Lys422). P4's cells exhibit short and dysfunctional telomeres similarly to other RTEL1-deficient patients. 3D structure predictions indicated that the p.Ile398_Lys422 deletion affects a part of the helicase ARCH domain, which lines the pore formed with the core HD and the iron-sulfur cluster domains and is highly specific of sequences from the eukaryotic XPD family members.


ARCH domain; Hoyeraal-Hreidarsson syndrome; RTEL1; Telomere; XPD

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