Human RTEL1 deficiency causes HoyeraalHreidarsson syndrome with short telomeres and genome instability

被引:137
作者
Le Guen, Tangui [1 ,2 ]
Jullien, Laurent [1 ,2 ]
Touzot, Fabien [1 ,2 ,3 ]
Schertzer, Michael [5 ]
Gaillard, Laetitia [1 ,2 ]
Perderiset, Mylene [5 ]
Carpentier, Wassila [6 ]
Nitschke, Patrick [2 ]
Picard, Capucine [2 ,3 ,4 ]
Couillault, Gerard [8 ]
Soulier, Jean [9 ]
Fischer, Alain [1 ,2 ,3 ]
Callebaut, Isabelle [7 ]
Jabado, Nada [10 ,11 ]
Londono-Vallejo, Arturo [5 ]
de Villartay, Jean-Pierre [1 ,2 ,3 ]
Revy, Patrick [1 ,2 ]
机构
[1] INSERM, U768, F-75015 Paris, France
[2] Univ Paris 05, Inst Imagine, Univ Sorbonne Paris Cite, Paris, France
[3] Necker Enfants Malades Hosp, AP HP, Serv Immunol & Hematol Pediat, Paris, France
[4] Necker Enfants Malades Hosp, AP HP, Study Ctr Primary Immunodeficiencies, Paris, France
[5] Inst Curie, Telomeres & Canc Lab, Paris, France
[6] Univ Paris 06, Plateforme Postgenom Pitie Salpetriere P3S, Paris, France
[7] Univ Paris 06, CNRS, UMR7590, IMPMC, Paris, France
[8] CHU Bocage, Serv Pediat, Dijon, France
[9] Univ Paris 07, INSERM, U944, Inst Univ Hematol, Paris, France
[10] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada
[11] McGill Univ, Dept Expt Med, Montreal, PQ H3Z 2Z3, Canada
基金
欧洲研究理事会;
关键词
DYSKERATOSIS-CONGENITA; CEREBELLAR HYPOPLASIA; DNA-REPLICATION; HELICASE; MUTATIONS; PATIENT; END;
D O I
10.1093/hmg/ddt178
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
HoyeraalHreidarsson 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.
引用
收藏
页码:3239 / 3249
页数:11
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