title: Mutation of POLB causes lupus in mice.
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.
authors.affiliation: 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.
authors.forename: Alireza G
authors.initials: AG
authors.lastname: Senejani
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Dawit
authors.initials: D
authors.lastname: Kidane
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Maher
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Zeiss
authors.affiliation: Department of Life Science, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Hong-Jae
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: McNiff
authors.affiliation: School of Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: 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.
authors.forename: Joann B
authors.initials: JB
authors.lastname: Sweasy
mesh_terms: D000818:Animals; D019951:DNA Polymerase beta / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D060152:V(D)J Recombination
chemical_list: D019951:DNA Polymerase beta