Volume 16 Supplement 1
DNA repair in lupus
© Xu et al.; licensee BioMed Central Ltd. 2014
Published: 18 September 2014
The myriad of mouse genetic alterations that result in a lupus-like phenotype and the >100 genes now known to be involved in human lupus are all probably only a hint at the potential complexity of the many mechanisms that lead to systemic lupus erythematosus (SLE).
We have applied exome sequencing to 24 SLE patients and their parents (trios) in an effort to conquer the data analysis and to identify candidate genes that may contribute when the activity of their gene products were substantially altered.
The proband of one of our SLE trios had de novo mutations in RAD54B that was predicted to change ARG to GLN and to be severely damaging to protein product activity by multiple algorithms. A second much more conservative de novo mutation in DOCK8 was not predicted to be consequential. RAD54B is a component of the homologous recombination DNA repair pathway. Cells from the SLE proband were unusually sensitive to ionizing radiation by the colony survival and comet tail assays. Ionizing radiation selectively induced interferon responsive genes in cells from this patient and not from controls. Transfection of the wild-type gene into the cells from this patient led to overexpression of the RAD54B gene product and returned ionizing radiation resistance toward normal.
These data in addition to the other five other genes directly or indirectly involved in altering risk of SLE by influencing DNA repair (TREX1, RAD51B, XRCC1, XRCC3, and XRCC4) implicate base excision repair, nonhomologous end joining, and homologous recombination. These results suggest that multiple DNA repair mechanisms contribute to SLE susceptibility.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.