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

被引：140

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

来源：

HUMAN MOLECULAR GENETICS | 2013年 / 22卷 / 16期

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

页码：3239 / 3249

页数：11

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