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Cell Rep. 2014 Jan 16;6(1):1-8. doi: 10.1016/j.celrep.2013.12.017. Epub 2014 Jan 2.

Mutation of POLB causes lupus in mice.

Author information

1
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
2
Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
5
Department of Life Science, Hanyang University, Seoul 133-791, Republic of Korea.
6
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
7
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
8
School of Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
9
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: joann.sweasy@yale.edu.

Abstract

A replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.

PMID:
24388753
PMCID:
PMC3916967
DOI:
10.1016/j.celrep.2013.12.017
[Indexed for MEDLINE]
Free PMC Article
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