A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model
Open accessAbstract
Objective It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model. Methods In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/+ mice was performed in the German Mouse Clinic. Results A novel missense mutation in the phospholipase Cγ2 gene (Plcg2) was identified in Ali14/+ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/+ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell ratio, up-regulation of Ig, alterations in body composition, and a reduction in cholesterol and triglyceride levels in peripheral blood. In addition, spermatozoa from Ali14/+ mice failed to fertilize eggs in vitro, despite the normal fertility of the Ali14/+ male mice in vivo. Conclusion These results suggest that the Plcg2-mediated pathways play…
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Ali14 mutant mice have a Y to C missense mutation in PLCγ2 at amino acid position 495 within the SH2 domain.
“Further work utilizing N-ethyl-N-nitrosourea alkylating mutagenesis resulted in the creation of the Ali14 mutant mice, in which gene mapping revealed a Y to C missense mutation in PLCγ2 at amino acid position 495 within the SH2 domain (107).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [107]
Ali14 mice exhibit a dominantly inherited disease characterized by spontaneous hind paw swelling/inflammation.
“These mice exhibited a dominantly inherited disease characterized by spontaneous hind paw swelling/inflammation (107).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [107]
Ali14 mice have hyperactive calcium flux in B cells, abnormally high T:B cell ratio especially in peripheral blood, and increased serum Ig, cholesterol, and triglycerides.
“Hyperactive calcium flux was observed in their B cells, with an abnormally high T:B cell ratio, especially in the peripheral blood, as well as increased serum Ig, cholesterol, and triglycerides (107).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [107]
The majority of hypermorphic variants (S707Y, Y495C, D993G) have been identified in the context of APLAID disorders, and in some mouse models with autoinflammatory phenotypes.
“the majority of hypermorphic variants (S707Y, Y495C, D993G) have been identified in the context of APLAID disorders, and in some mouse models with autoinflammatory phenotypes [3, 109, 110]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [109]
Different degrees of severity have been described for mouse models bearing hypermorphic spontaneous mutations (Ali14 and Ali5).
“Different degrees of severity have also been described for mouse models bearing hypermorphic spontaneous mutations (Ali14 and Ali5 [109, 112])”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [109]
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References 46 · Cited by 46
- Authors
- Abe, K., Fuchs, H., Boersma, A., Hans, W., Yu, P., Kalaydjiev, S., Klaften, M., Adler, T., Calzada‐Wack, J., Mossbrugger, I., Rathkolb, B., Rozman, J., Prehn, C., Maraslioglu, M., Kametani, Y., Shimada, S., Adamski, J., Busch, D. H., Esposito, I., Klingenspor, M., Wolf, E., Wurst, W., Gailus‐Durner, V., Katan, M., Marschall, S., Soewarto, D., Wagner, S., & de Angelis, M. H.
- Affiliations
- Tokai University (JP)
- Helmholtz Munich (DE)
- Philipps University of Marburg (DE)
- Technical University of Munich (DE)
- ORCID
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2011-04-27
- Volume
- 63
- Issue
- 5
- Pages
- 1301-1311
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- OpenAlex
- W2039175743
- Cited by
- 46
- References
- 46
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 3 · 2019: 2 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 2.81
- Type
- journal article
- Language
- en
- Open access
- green
- mediatum.ub.tum.de
- Licence
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (22500392)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- PLCγ2, N-ethyl-N-nitrosourea mutagenesis, inflammatory arthritis, gain-of-function mutations, metabolic defects, male infertility, sperm fertilization, systemic inflammatory disease, mouse model
- MeSH terms
- Animals, Arthritis, Experimental, Body Composition, Ethylnitrosourea, Flow Cytometry, Infertility, Male, Male, Mice, Mutant Strains, Mutation, Sperm Motility, Mutagenesis, Polymorphism, Single Nucleotide, Mice, Phospholipase C gamma
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