Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency

Silva, Karina Ribeiro da; Fraga, Tatiana R.; Lucatelli, Juliana Faggion; Grumach, Anete Sevciovic; Isaac, Lourdes

doi:10.1016/j.imbio.2016.01.005

Cited by 8 publications

(9 citation statements)

References 51 publications

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“…None of these studies looked for a haplotype association within C3 . Intronic variants causing C3 splicing mutations have been described in patients with C3 deficiency due to exon deletion from the C3 mRNA (40, 41). The current study is according to our knowledge the first one to show a disease association in C3 with a haplotype-based mechanism instead of the conventional single SNP association.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

et al. 2017

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Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.

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Section: Discussionmentioning

confidence: 99%

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

et al. 2017

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“…In addition to infections, renal and lupus‐like diseases have been reported in 25% and 15% of C3‐deficient patients, respectively . To date, 40 cases of complete deficiency of C3 have been described worldwide, of which 21 have had the clinical diagnosis validated by molecular analysis . Notably, the onset of symptoms starts at about 2 years of age, and by the time of the case reports, 29% of the patients have had at least one sibling die at a very young age (less than 2 years old), indicating a critical role for C3 in childhood, when the adaptive immune system and antibody responses are not fully developed .…”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinical mentioning

confidence: 99%

“…Although FI or FH deficiency is generally associated with increased susceptibility to infections, the presence of C3‐Nef or functional defects in FH are mainly correlated with kidney diseases such as C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS), reflecting the pivotal role of FH in the regulation of complement activation . Evidence acquired from a healthy individual presenting with an abnormally low concentration of C3 in circulation, as a result of having one functional and one null C3 allele, indicates that C3 concentrations of 0.18 mg/mL (approximately 18% of normal C3 levels) are sufficient to maintain a proper activation of complement response and avoid complement‐related diseases …”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinical mentioning

confidence: 99%

“…146,147 To date, 40 cases of complete deficiency of C3 have been described worldwide, of which 21 have had the clinical diagnosis validated by molecular analysis. [146][147][148][149] Notably, the onset of symptoms starts at about 2 years of age, and by the time of the case reports, 29% of the patients have had at least one sibling die at a very young age (less than 2 years old), indicating a critical role for C3 in childhood, when the adaptive immune system and antibody responses are not fully developed. 150 Interestingly, a recent report describing 41 French patients who were diagnosed with distinct complement deficiencies during adulthood did not include any C3-deficient patients.…”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinicamentioning

confidence: 99%

“…146,[158][159][160] Evidence acquired from a healthy individual presenting with an abnormally low concentration of C3 in circulation, as a result of having one functional and one null C3 allele, indicates that C3 concentrations of 0.18 mg/mL (approximately 18% of normal C3 levels) are sufficient to maintain a proper activation of complement response and avoid complement-related diseases. 148 Now that the development of complement therapeutics is in vogue, with numerous compounds in or close to the clinical phase for various diseases, 145,161,162 it is worth considering the biological impact of the therapeutic inhibition of C3. Such an approach commonly raises concerns over infections in the treated individuals.…”

Section: Too Much Too Little: Disturbed C3 Balance and Its Clinicamentioning

confidence: 99%

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Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Ricklin

Reis

Mastellos

et al. 2016

Immunological Reviews

349

295

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Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.

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Complement Deficiencies

Grumach¹,

Kirschfink²

2022

Encyclopedia of Infection and Immunity

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Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency

Cited by 8 publications

References 51 publications

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Complement Deficiencies

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