C1QTNF4 gene p.His198Gln mutation is correlated with early‐onset systemic lupus erythematosus in Iranian patients

Wen

et al. 2021

Genes

Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr (that manifest lupus-like phenotype) and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the Phosphoinositide 3-kinase (PI3K)-AKT pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and, therefore, promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models.

Section: Discussionsupporting

confidence: 85%

Remodeling of Neurotransmission, Chemokine, and PI3K-AKT Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus

Wen

et al. 2021

Genes

“…Exome sequencing of individuals with a severe form of the autoimmune disease systemic lupus erythematosus (SLE) also identified a rare variant of CTRP4 / C1QTNF4 (H198Q) which encodes a protein that can reduce TNF‐α‐mediated NF‐κB activation and cell death in vitro 44 . Whether this rare variant, also identified in a separate cohort of SLE patients, 45 is causally linked to SLE remains to be established. In other brain inflammatory condition due to infection, such as herpes simplex encephalitis, expression of CTRP4 was shown to be upregulated 46 .…”

Section: Introductionmentioning

confidence: 99%

CTRP4 ablation impairs associative learning and memory

Sarver

Cheng

et al. 2021

The FASEB Journal

C1q/TNF-related protein (CTRP) family comprises fifteen highly conserved secretory proteins with diverse central and peripheral functions. In zebrafish, mouse, and human, CTRP4 is most highly expressed in the brain. We previously showed that CTRP4 is a metabolically responsive regulator of food intake and energy balance, and mice lacking CTRP4 exhibit sexually dimorphic changes in ingestive behaviors and systemic metabolism. Recent single-cell RNA sequencing also revealed Ctrp4/C1qtnf4 expression in diverse neuronal cell types across distinct anatomical brain regions, hinting at additional roles in the central nervous system not previously characterized. To uncover additional central functions of CTRP4, we subjected Ctrp4 knockout (KO) mice to a battery of behavioral tests. Relative to wild-type (WT) littermates, loss of CTRP4 does not alter exploratory, anxiety-, or depressive-like behaviors, motor function and balance, sensorimotor gating, novel object recognition, and spatial memory. While pain-sensing mechanisms in response to thermal stress and mild shock are intact, both male and female Ctrp4 KO mice have increased sensitivity to pain induced by higher-level shock, suggesting altered nociceptive function. Importantly, CTRP4 deficiency impairs hippocampal-dependent associative learning and memory as assessed by trace fear conditioning paradigm. This deficit is sex-dependent, affects only female mice, and is associated with altered expression of learning and memory genes (Arc, c-fos, and Pde4d) in the hippocampus and cortex. Altogether, our behavioral and gene expression analyses have uncovered novel aspects of the CTRP4 function and provided a physiological context to further investigate its mechanism of action in the central and peripheral nervous system.

“…Deleterious mutations in lipopolysaccharide-responsive beige-like anchor (LRBA) genes lead to its deficiency which was found to be associated with juvenile lupus [ 59 ]. Mutation (p.His198Gln) in the C1QTNF4 gene was found to be potentially involved in SLE risk in the Iranian population [ 60 ]. Current evidence in the genetic susceptibility of lupus shows that genes can also potentially regulates the dysregulated immunological mechanisms associated with disease manifestation that will be further modified through various epigenetic phenomenon.…”

Section: Genetic Factorsmentioning

confidence: 99%

Systemic lupus erythematosus: latest insight into etiopathogenesis

et al. 2023

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder of unknown etiology. Multifactorial interaction among various susceptible factors such as environmental, hormonal, and genetic factors makes it more heterogeneous and complex. Genetic and epigenetic modifications have been realized to regulate the immunobiology of lupus through environmental modifications such as diet and nutrition. Although these interactions may vary from population to population, the understanding of these risk factors can enhance the perception of the mechanistic basis of lupus etiology. To recognize the recent advances in lupus, an electronic search was conducted among search engines such as Google Scholar and PubMed, where we found about 30.4% publications of total studies related to genetics and epigenetics, 33.5% publications related to immunobiology and 34% related to environmental factors. These outcomes suggested that management of diet and lifestyle have a direct relationship with the severity of lupus that influence via modulating the complex interaction among genetics and immunobiology. The present review emphasizes the knowledge about the multifactorial interactions between various susceptible factors based on recent advances that will further update the understanding of mechanisms involved in disease pathoetiology. Knowledge of these mechanisms will further assist in the creation of novel diagnostic and therapeutic options.