Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Blood Advances
Fabien TouzotPatrick Revy

Abstract

Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical ...Continue Reading

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Citations

Jan 19, 2018·Blood Advances·Judith C W MarshGhulam J Mufti
Sep 16, 2020·Journal of Hematology & Oncology·Yuanliang YanZhijie Xu
Jul 22, 2018·Nature Immunology·Eric VivierAlain Fischer
Jul 28, 2020·Journal of Clinical Immunology·Alma ZivDror S Shouval
May 14, 2020·Nature Structural & Molecular Biology·A TakedachiP H L Gaillard
May 23, 2021·Nature Communications·Fiorella GhisaysJohn H J Petrini

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