ERCC6L2 Mutations Link a Distinct Bone-Marrow-Failure Syndrome to DNA Repair and Mitochondrial Function

Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and...

Full description

Saved in:
Bibliographic Details
Published in:American journal of human genetics 2014-02, Vol.94 (2), p.246-256
Main Authors: Tummala, Hemanth, Kirwan, Michael, Walne, Amanda J., Hossain, Upal, Jackson, Nicholas, Pondarre, Corinne, Plagnol, Vincent, Vulliamy, Tom, Dokal, Inderjeet
Format: Article
Language:English
Subjects:
Acetylcysteine - metabolism
Anemia, Aplastic
Bone marrow
Bone Marrow Diseases
Bone Marrow Failure Disorders
Cell Line, Tumor
Cell Nucleus - genetics
Cell Nucleus - metabolism
Cell Survival - drug effects
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA damage
DNA Damage - drug effects
DNA Helicases - genetics
DNA Repair - genetics
Female
Gene Knockdown Techniques
HEK293 Cells
HeLa Cells
Hemoglobinuria, Paroxysmal - genetics
Histones - genetics
Histones - metabolism
Humans
Male
Mitochondria - drug effects
Mitochondria - genetics
Mitomycin - toxicity
Mutation
Neurological disorders
Pedigree
Phosphorylation
Reactive Oxygen Species
Sesquiterpenes - toxicity
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2014.01.007