Dataset Information

A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus-like Disease in Mice.

ABSTRACT:

Objective

To determine if single-nucleotide polymorphisms (SNPs) in DNA repair genes are enriched in individuals with systemic lupus erythematosus (SLE) and if they are sufficient to confer a disease phenotype in a mouse model.

Methods

Human exome chip data of 2499 patients with SLE and 1230 healthy controls were analyzed to determine if variants in 10 different mismatch repair genes (MSH4, EXO1, MSH2, MSH6, MLH1, MSH3, POLH, PMS2, ML3, and APEX2) were enriched in individuals with SLE. A mouse model of the MSH6 SNP, which was found to be enriched in individuals with SLE, was created using CRISPR/Cas9 gene targeting. Wildtype mice and mice heterozygous and homozygous for the MSH6 variant were then monitored for 2 years for the development of autoimmune phenotypes, including the presence of high levels of antinuclear antibodies (ANA). Additionally, somatic hypermutation frequencies and spectra of the intronic region downstream of the V_H J558-rearranged J_H4 immunoglobulin gene was characterized from Peyer's patches.

Results

Based on the human exome chip data, the MSH6 variant (rs63750897, p.Ser503Cys) is enriched among patients with SLE versus controls after we corrected for ancestry (odds ratio = 8.39, P = 0.0398). Mice homozygous for the MSH6 variant (Msh6^S502C/S502C ) harbor significantly increased levels of ANA. Additionally, the Msh6^S502C/S502C mice display a significant increase in the infiltration of CD68+ cells (a marker for monocytes and macrophages) into the lung alveolar space as well as apoptotic cells. Furthermore, characterization of somatic hypermutation in these mice reveals an increase in the DNA polymerase η mutational signature.

Conclusion

An MSH6 mutation that is enriched in humans diagnosed with lupus was identified. Mice harboring this Msh6 mutation develop increased autoantibodies and an inflammatory lung disease. These results suggest that the human MSH6 variant is linked to the development of SLE.

SUBMITTER: Meas R

PROVIDER: S-EPMC9469486 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus-like Disease in Mice.

Meas Rithy R Nititham Joanne J Taylor Kimberly E KE Maher Stephen S Clairmont Kaylyn K Carufe Kelly E W KEW Kashgarian Michael M Nottoli Timothy T Cheong Ana A Nagel Zachary D ZD Gaffney Patrick M PM Criswell Lindsey A LA Sweasy Joann B JB

ACR open rheumatology 20220616 9

<h4>Objective</h4>To determine if single-nucleotide polymorphisms (SNPs) in DNA repair genes are enriched in individuals with systemic lupus erythematosus (SLE) and if they are sufficient to confer a disease phenotype in a mouse model.<h4>Methods</h4>Human exome chip data of 2499 patients with SLE and 1230 healthy controls were analyzed to determine if variants in 10 different mismatch repair genes (MSH4, EXO1, MSH2, MSH6, MLH1, MSH3, POLH, PMS2, ML3, and APEX2) were enriched in individuals with ...[more]

PMID: 35708944

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Project description:ObjectivesCD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT).MethodsCross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B.ResultsOf the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42' vs. 297 ± 50' in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008).ConclusionsSLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B.

Dataset Information

A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus-like Disease in Mice.

Objective

Methods

Results

Conclusion

Publications

A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus-like Disease in Mice.

Similar Datasets

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