共 33 条
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.
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页码:3239 / 3249
页数:11
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