Mutation of POLB causes lupus in mice

Alireza G. Senejani; Yanfeng Liu; Dawit Kidane; Stephen E. Maher; Caroline J. Zeiss; Hong Jae Park; Michael Kashgarian; Jennifer M. McNiff; Daniel Zelterman; Alfred L.M. Bothwell; Joann B. Sweasy

doi:10.1016/j.celrep.2013.12.017

Mutation of POLB causes lupus in mice

Alireza G. Senejani, Yanfeng Liu, Dawit Kidane, Stephen E. Maher, Caroline J. Zeiss, Hong Jae Park, Michael Kashgarian, Jennifer M. McNiff, Daniel Zelterman, Alfred L.M. Bothwell, Joann B. Sweasy

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45 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1-8
Number of pages	8
Journal	Cell Reports
Volume	6
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2013.12.017
State	Published - 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2013.12.017

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@article{9ef8539ed8014a63bcba87fc7186a8b3,

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.",

author = "Senejani, {Alireza G.} and Yanfeng Liu and Dawit Kidane and Maher, {Stephen E.} and Zeiss, {Caroline J.} and Park, {Hong Jae} and Michael Kashgarian and McNiff, {Jennifer M.} and Daniel Zelterman and Bothwell, {Alfred L.M.} and Sweasy, {Joann B.}",

note = "Funding Information: This research was supported by grant ES019179 from the National Institute of Environmental Health Sciences. ",

year = "2014",

doi = "10.1016/j.celrep.2013.12.017",

language = "English (US)",

volume = "6",

pages = "1--8",

journal = "Cell Reports",

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publisher = "Cell Press",

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TY - JOUR

T1 - Mutation of POLB causes lupus in mice

AU - Senejani, Alireza G.

AU - Liu, Yanfeng

AU - Kidane, Dawit

AU - Maher, Stephen E.

AU - Zeiss, Caroline J.

AU - Park, Hong Jae

AU - Kashgarian, Michael

AU - McNiff, Jennifer M.

AU - Zelterman, Daniel

AU - Bothwell, Alfred L.M.

AU - Sweasy, Joann B.

N1 - Funding Information: This research was supported by grant ES019179 from the National Institute of Environmental Health Sciences.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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JO - Cell Reports

JF - Cell Reports

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Mutation of POLB causes lupus in mice

Abstract

ASJC Scopus subject areas

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