C1QA Gene Research Articles

Monogenic lupus with neuroregression in an infant due to rare compound heterozygous variants in C1QA gene: Case based review.

Monogenic lupus is a rare variant of systemic lupus erythematosus (SLE) that develops in patients with a single gene disorder. Early complement component deficiencies were the first forms of monogenic lupus to be described and C1Q gene mutations are one of the most common forms. C1QA complement deficiency has been reported to occur usually due to biallelic variants in C1QA gene and compound heterozygous variants in C1QA gene have rarely been reported. Majority of the monogenic lupus patients with C1Q deficiency present with mucocutaneous, renal, and musculoskeletal manifestations. Our patient is an unusual case of monogenic lupus with severe neurological manifestations along with cutaneous, haematological, and hepatic manifestations secondary to rare compound heterozygous variants in C1QA gene and anti-ribosomal P autoantibody positivity. She was treated with glucocorticoids, rituximab and fresh frozen plasma with partial neurological recovery. Thus, we present a unique case of monogenic lupus due to a rare compound heterozygous variant in C1QA gene with a brief review of literature.

Design of siRNAs Against Immune-Implicated Atherosclerosis Genes: Computational Study

Atherosclerosis is a chronic, immune-implicated, disease with high numbers of mortality globally. The aim of the current study is to target these genes by specific siRNA utilizing bioinformatics tools. Eight siRNAs were designed via RNAxs from C1QA and ITBG2 gene sequences retrieved from NCBI database. GC% and Tm of siRNAs were calculated through OligoCalc web interface. In addition, hybridization energy of siRNAs with the corresponding target sequences as well as docking to argonaute 2 protein were performed using DuplexFold and HDock. The designed siRNAs exhibited acceptable GC content and Tm values. Besides, the hybridization energy and docking scores were highly significant to block the expression of the mentioned genes. In conclusion, the designed siRNAs are superior candidates for silencing immune-mediated atherosclerotic genes which deserve further consideration.

Une étiologie rare de lupus érythémateux systémique

AbstractA 9-month-old infant consulted a dermatologist for facial rashes and mouth ulcerations. The initial assessment revealed lupus-type autoantibodies and the diagnosis of systemic lupus erythematosus was made at the age of 12 months. One year later, genetic results and in-depth complement analysis revealed C1q deficiency due to an autosomal recessive mutation in the C1QA gene. The patient was treated with hematopoietic stem cell transplantation which normalized C1q concentrations.

In silico analysis of missense variants of the C1qA gene related to infection and autoimmune diseases

ObjectivesC1q is a key activator of the classical pathway of the complement system and exerts consequences relating to opsonization and phagocytosis. The C1qA gene is one of three genes encoding the C1q molecule. Defects in C1q, and especially in C1qA, have been linked to an increased susceptibility to infection, sepsis, and systemic lupus erythematosus. These defects could arise from missense single nucleotide polymorphisms (SNPs) and their deleterious impacts on protein structure and function. Thus, identifying high-risk missense SNPs in C1qA has become a necessity if we are to identify appropriate measures for prevention and management of affected patients. MethodsA comprehensive in silico study was conducted to screen the 184 missense SNPs in the C1qA gene using different tools with different algorithms and approaches. We investigated the impact of SNPs on protein function, stability, and structure. In addition, we identified the location of the SNPs on protein domains, secondary structure alignment, and the phylogenetic conservation of their positions. ResultsOf the 184 missense SNPs, 10 SNPs were predicted to be the most damaging to protein function and structure. ConclusionTen missense SNPs were predicted to have the highest risk of damaging protein function and structure, thus leading to infection, sepsis, and systemic lupus erythematosus. These 10 SNPs constitute the best candidates for further experimental investigations.

Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-\u03b3-dependent manner

BackgroundIt has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes.MethodsExpression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation.ResultsNeuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1β) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism.ConclusionOur results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.

Low-Intensity Exercise in Mice Is Sufficient to Protect Retinal Function During Light-Induced Retinal Degeneration.

PurposeWe previously reported that a specific treadmill running exercise regimen protects against light-induced retinal degeneration (LIRD) in mice. We hypothesized that this protective effect varies with running intensity. To test this, mice undergoing LIRD were run at different treadmill speeds and retinal function was assessed.MethodsBALB/c mice were assigned to LIRD groups at varying treadmill speeds—0, 5, 10, or 20 m/min labeled inactive, low, medium, and high, respectively—and compared with naïve mice exposed to standard lighting (50 lux; naïve). Following 2 weeks of exercise, a subset of mice were exposed to toxic light (10,000 lux; LIRD) for 4 hours. After 5 additional days of exercise, retinal function was assessed by ERG. Corticosterone levels in serum and cathepsin B (CTSB) protein levels in muscle, brain, serum, and retina were measured. The retinal gene expression of complement factor 1qa (C1qa) and CTSB were measured.ResultsThe low+LIRD and medium+LIRD exercise groups had greater a- and b-wave ERG amplitudes when compared with the inactive+LIRD group (P < 0.02). The high+LIRD mice only differed from the inactive+LIRD mice in their dark-adapted b-waves. Serum corticosterone increased in the high+LIRD mice (P < 0.006). Retinal CTSB protein levels were higher in the low+LIRD versus high+LIRD mice (P < 0.004) but were otherwise unchanged. Exercise of any intensity decreased C1qa gene expression.ConclusionsFaster running did not additionally protect against LIRD, but it did increase serum corticosterone, suggesting stress-induced limits to exercise benefits. Unexpectedly, exercise did not increase CTSB proteins levels in muscle or serum, suggesting that it may not mediate exercise effects. Our results have implications for the use of low-intensity exercise as a vision loss treatment.

C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.

ObjectivesTransthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age‐at‐onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR‐FAP Val30Met Portuguese patients.MethodsWe analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the non‐independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions.ResultsTwo variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later‐onset.Interpretation C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR‐FAP Val30Met.

Exome sequencing revealed C1Q homozygous mutation in Pediatric Systemic Lupus Erythematosus

Introduction and objectivesPediatric Systemic Lupus Erythematosus (pSLE) is an autoimmune disorder of children. Early disease onset raises the probability of genetic etiology and it is more severe than adult SLE. Patients and methodsHerein an eight-year-old girl with pSLE from consanguineous parents is reported. ResultsAlthough she was diagnosed as pSLE since the age of two years, Whole Exome Sequencing (WES) revealed a rare stop-gained C>T mutation in C1QA gene. The variant was validated and segregated in patient and the family. Furthermore, serum levels of the C1q protein were measured and found to be much lower than normal ranges. ConclusionsThis study indicated that C1Q deficiency should be considered as a differential diagnosis of pSLE. Therefore, measurement of C1q should be recommended in all cases with pSLE.

C1QA gene mutations in a pediatric SLE cohort from North India

The objective of this study was to report the 1-year follow-up study results of the new Horizon stent graft (Endospan, Herzliya, Israel) from two different prospective consecutive trials. The Horizon abdominal aortic aneurysm stent graft system is a 14F profile system requiring only a single access site. It consists of three modules, introduced separately: base limb (iliac to iliac limb); distal aortic limb; and proximal aortic limb with a bare suprarenal crown and active fixation.Data from the first in man (FIM) clinical study with 10 patients enrolled and the pivotal study with 30 patients were analyzed. Outcomes measured were freedom from major adverse events (MAEs) including all-cause mortality, myocardial infarction, renal failure, respiratory failure, paraplegia, stroke, bowel ischemia, and procedural blood loss ≥1000 mL. Performance end points included successful delivery and deployment of the device, freedom from aneurysm growth ≥5 mm, type I or type III endoleak, stent graft occlusion, conversion to open surgery, rupture, and stent graft migration.In the FIM study, one conversion to open surgery with >1000 mL of blood loss was registered perioperatively. In the pivotal study, no perioperative MAE was registered. Overall, at 1-year follow-up, two deaths and one aneurysm growth unrelated to endoleak were registered.The results of both the FIM and pivotal studies demonstrated that 39 of 40 procedures were successful for delivery and deployment of the Horizon stent graft. No MAE was registered during the follow-up. The primary safety and performance end points were met in both studies.

Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain

BackgroundThe complement cascade not only provides protection from infection but can also mediate destructive inflammation. Complement is also involved in elimination of neuronal synapses which is essential for proper development, but can be detrimental during aging and disease. C1q, required for several of these complement-mediated activities, is present in the neuropil, microglia, and a subset of interneurons in the brain.MethodsTo identify the source(s) of C1q in the brain, the C1qa gene was selectively inactivated in the microglia or Thy-1+ neurons in both wild type mice and a mouse model of Alzheimer’s disease (AD), and C1q synthesis assessed by immunohistochemistry, QPCR, and western blot analysis.ResultsWhile C1q expression in the brain was unaffected after inactivation of C1qa in Thy-1+ neurons, the brains of C1qaFL/FL:Cx3cr1CreERT2 mice in which C1qa was ablated in microglia were devoid of C1q with the exception of limited C1q in subsets of interneurons. Surprisingly, this loss of C1q occurred even in the absence of tamoxifen by 1 month of age, demonstrating that Cre activity is tamoxifen-independent in microglia in Cx3cr1CreERT2/WganJ mice. C1q expression in C1qaFL/FL: Cx3cr1CreERT2/WganJ mice continued to decline and remained almost completely absent through aging and in AD model mice. No difference in C1q was detected in the liver or kidney from C1qaFL/FL: Cx3cr1CreERT2/WganJ mice relative to controls, and C1qaFL/FL: Cx3cr1CreERT2/WganJ mice had minimal, if any, reduction in plasma C1q.ConclusionsThus, microglia, but not neurons or peripheral sources, are the dominant source of C1q in the brain. While demonstrating that the Cx3cr1CreERT2/WganJ deleter cannot be used for adult-induced deletion of genes in microglia, the model described here enables further investigation of physiological roles of C1q in the brain and identification of therapeutic targets for the selective control of complement-mediated activities contributing to neurodegenerative disorders.

The GG rs292001 genotype prevails in seronegative for ANA and anti-dsDNA antibodies patients with lupus nephritis

Rs292001 is single nucleotide polymorphism in non-coding regions of C1QA gene. C1q is subcomponent of the C1 first component of the classical pathway of complement activation. Rs292001 was investigated for association with some conventional immunological markers of lupus nephritis activity in SLE patients – levels of C1q, C3, C4, anti-C1q, anti-nuclear (ANA) and anti-dsDNA autoantibodies. Genomic DNA was isolated from peripheral blood of 18 patients with biopsy-proven lupus nephritis (LN). SNP genotyping for the presence of rs292001 was performed by quantitive real-time PCR method. Presence of complement C1q, C3 and C4 and anti-C1q autoantibodies was screened by ELISA. ANA and anti-dsDNA antibodies were detected by indirect immunofluorescence. We found that GG rs292001 genotype prevailed in seronegative for ANA and anti-dsDNA antibodies LN patients (p=0.008; p<0.012). The AA rs292001 genotype showed a trend towards lower serum C1q levels. These results reaffirm a previously established probable protective role of G allele against the clinical activity of the SLE.

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

Early Complement Component Deficiency in a Single-Centre Cohort of Pediatric Onset Lupus.

To assess complement levels C1q, C2, C3 and C4 in children with pediatric-onset lupus during the quiescent stage of disease. Thirty-four consecutive children with pediatric-onset SLE (onset below 12years), in the quiescent stage were enrolled for the study. Twenty-nine age and sex matched healthy children were also enrolled for the purpose of comparison. Complement C1q and C2 levels were estimated by enzyme-linked immunosorbent assay (ELISA) whereas C3 and C4 were measured by end-point nephelometry. Genetic mutation analysis and functional assessment of classical complement pathway by ELISA were carried out in children with depressed levels of these complements. The study protocol was approved by the Institute Thesis Committee and the Institute Ethics Committee. Mean complement C1q, C2, C3 and C4 levels were 50.32, 17.28, 1320 and 236mg/L respectively. Levels of complements were low in 7/34 children with SLE. An early age at onset, low anti-dsDNA titres and predominant skin manifestations were noted in children with decreased levels of complement C1q. Mutation analysis of C1qA gene revealed a homozygous nonsense mutation: C1QA (NM_015991) c.622C>T, p.Q208X in one child. A homozygous acceptor splice site mutation at the -2 position of intron2 of C1QA (c.164-2A>C) was detected in another child. The age at onset of disease was early in both these children, at 2.5 and 1.5years respectively. Children with inherited deficiency of C1q and other early complement components present with early onset lupus that has a distinct clinical and immunological profile.

Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling.

Hypertension induces structural remodelling of arteries, which leads to arteriosclerosis and end-organ damage. Hyperplasia of vascular smooth muscle cells (VSMCs) and infiltration of immune cells are the hallmark of hypertensive arterial remodelling. However, the precise molecular mechanisms of arterial remodelling remain elusive. We have recently reported that complement C1q activates β-catenin signalling independent of Wnts. Here, we show a critical role of complement C1-induced activation of β-catenin signalling in hypertensive arterial remodelling. Activation of β-catenin and proliferation of VSMCs were observed after blood-pressure elevation, which were prevented by genetic and chemical inhibition of β-catenin signalling. Macrophage depletion and C1qa gene deletion attenuated the hypertension-induced β-catenin signalling, proliferation of VSMCs and pathological arterial remodelling. Our findings unveil the link between complement C1 and arterial remodelling and suggest that C1-induced activation of β-catenin signalling becomes a novel therapeutic target to prevent arteriosclerosis in patients with hypertension.

THU0025 Complement Deficiencies in A Cohort of Pediatric Onset Lupus: A Preliminary Study from A Tertiary Care Centre in North India

BackgroundDeficiency of the early components of the classical complement pathway (C1q, C1r, C1s, C4 and C2) is the strongest single genetic predisposing risk factor for the development of Systemic lupus...

SAT0431 Molecular Characterization of Complement C1Q, C2, and C4 Genes in Juvenile Systemic Lupus Erythematosus

BackgroundIt was not already defined whether standard measures are sufficient to asses primary C1q, C2 and C4 deficiencies1-3.ObjectivesTo perform C1q, C2 and C4 molecular characterization in Juvenile Systemic Lupus Erythematosus...

Abstract 8885: C1q-induced Activation of Wnt Signaling Triggers Hypertensive Arterial Remodeling

Hypertension is the leading risk factor of many cardiovascular diseases, and the structural remodeling of arteries in response to elevated blood pressure (hypertensive arterial remodeling) contributes to the end-organ damage associated with hypertension. The signaling mechanism that initiates hypertensive arterial remodeling remains elusive. Here we show that complement C1q-induced activation of Wnt signaling plays a critical role in arterial remodeling associated with hypertension. In the early phase of hypertension, proliferation of vascular smooth muscle cells (VSMCs) and activation of canonical Wnt signaling in VSMCs were observed, and inhibition of canonical Wnt signaling suppressed hypertension-induced VSMC proliferation. Complement C1q was highly expressed in macrophages recruited to the vessel wall following blood pressure elevation, and depletion of macrophages attenuated hypertension-induced VSMC proliferation and activation of canonical Wnt signaling in VSMCs. Furthermore, both C1s inhibition and C1qa gene deletion suppressed activation of canonical Wnt signaling in VSMCs and VSMC proliferation in the early phase of hypertension, and prevented subsequent structural arterial remodeling in the chronic phase. Our findings collectively suggest that macrophage-derived C1q triggers hypertensive arterial remodeling through activation of canonical Wnt signaling in VSMCs. Inhibition of C1q-induced Wnt signal activation may be a novel therapeutic strategy to reduce cardiovascular complications in patients with hypertension.

Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.

Identification of novel coding mutation in C1qA gene in an African–American pedigree with lupus and C1q deficiency

Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

Association study ofC1qApolymorphisms with systemic lupus erythematosus in a Han population

The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the C1qA gene region with systemic lupus erythematosus (SLE) in a Chinese Han population. Chinese SLE patients (n = 748) and ethnically- and geographically-matched healthy controls (n = 750) were genotyped for the C1qA region SNPs, rs172378 and rs665691, by using the Sequenom MassArray system. The Chinese Han SLE patients and controls had statistically similar frequencies of alleles, genotypes, and haplotypes of C1qA polymorphisms. Moreover, no association signal was detected on different genetic models (additive, dominant, and recessive) or in SLE subgroups stratified by various clinical manifestations. The C1qA SNPs, rs172378 and rs665691, confer no genetic predisposition to SLE in a Chinese Han population.