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

Abstract

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 C␥2 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

Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie e.V.

“…In addition we showed that under normal growth conditions there is no evidence for lower cGMP concentrations in daf-11 mutants than in wild-type animals proposing that not only low cGMP levels are responsible for the extended lifespan of daf-11 mutants [1].…”

“…Daf-11 is one of the receptor-bound GCs in C. elegans and an ortholog of human particulate guanylyl cyclase A (pGC-A). pGC-A has not been shown yet to be in involved in mammalian oxidative stress response, but previous studies in C. elegans showed that daf-11 loss of function mutants have a significant higher life expectancy under normal and oxidative stress conditions than wild-type nematodes due to lower cGMP concentrations [1].…”

“…Mechanism of arginine-mediated regulation of human cationic amino acid transporters hCAT1 and hCAT-3 in T cells Amann E. 1 , The amino acid arginine is crucial for the activation of human T lymphocytes. Proliferation and cytokine release are reduced in the absence of arginine and thus the effector functions of T cells diminished.…”

“…Furthermore, even though all the inactive structures of GPCRs crystallized so far confirm the presence of the R 3.50 /D 3.49 interaction, most of them lack the expected interhelical R 3.50 /E 6.30 bond and do not clarify the role of the DRY motif and its interaction partners. Here, using a well characterized FRET-based technique [1,2], we examined the effects of the substitution of D 3.49 and E 6.30 on the α2A-AR conformation in real time. The results show that neutralization of these residues generates 2 distinct α2A-AR conformational states.…”

“…Protective effects of boric acid against lead-and cadmium-induced genotoxicity in vitro Behm C. 1 , Cadmium and lead compounds are well known hazards at workplaces and important environmental pollutants that can cause serious damage to human health. As the metal ions (Cd 2+ and Pb 2+ ) accumulate in the organism, there is special concern regarding chronic toxicity and damage to the genetic material.…”