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Ferri G.,University of Modena and Reggio Emilia | Corradini B.,University of Modena and Reggio Emilia | Estany-Gestal A.,University of Santiago de Compostela | Diz P.S.,University of Santiago de Compostela | And 3 more authors.
Forensic Science International: Genetics Supplement Series | Year: 2011

Suicide is a devastating psychopathological trait with familial transmission. According to epidemiological data suicide is partly under genetic influence. Despite the extensive body of association studies, to date genetic factors linked to suicide diathesis are largely unknown. In this study a set of 8 SNPs and a 43. bp ins/del was genotyped in an Italian sample of suicide completers (n= 65) and control subjects (n= 77). The selected markers are spread across multiple brain pathways: serotonergic, stress-related HPA axis, catecholamine metabolism and nitric oxide (NO) neurotransmission. Basic analysis at single loci shows significant differences in allele and genotype distributions between victims and controls for TPH1-rs1800532(allele A) and NOSI-rs693534(allele A), pointing to an association with the group of suicides. Presented results are intended to be exploratory, requiring further investigation in a larger sample size. Systematic efforts in suicide research is quite important in order to empower understanding of risk factors and developing preventive strategies in clinical practice. © 2011 Elsevier Ireland Ltd.

Chinchilla D.S.,CSIC - Biological Research Center | Chinchilla D.S.,Research Center Biomedica en Enfermedades Raras | Pinto S.,CSIC - Biological Research Center | Pinto S.,Research Center Biomedica en Enfermedades Raras | And 11 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2014

Background and objectives: Atypical hemolytic uremic syndrome is characterized by vascular endothelial damage caused by complement dysregulation. Consistently, complement inhibition therapies are highly effective in most patients with atypical hemolytic uremic syndrome. Recently, it was shown that a significant percentage of patients with early-onset atypical hemolytic uremic syndrome carry mutations in diacylglycerol kinase-e, an intracellular protein with no obvious role in complement. These data support an alternative, complement- independent mechanism leading to thrombotic microangiopathy that has implications for treatment of early-onset atypical hemolytic uremic syndrome. To get additional insights into this new form of atypical hemolytic uremic syndrome, the diacylglycerol kinase-e gene in a cohort with atypical hemolytic uremic syndrome was analyzed. Design, setting, participants, & measurements: Eighty-three patients with early-onset atypical hemolytic uremic syndrome (,2 years) enrolled in the Spanish atypical hemolytic uremic syndrome registry between 1999 and 2013 were screened for mutations in diacylglycerol kinase-e. These patients were also fully characterized for mutations in the genes encoding factorH,membrane cofactor protein, factor I, C3, factor B, and thrombomodulin CFHRs copy number variations and rearrangements, and antifactor H antibodies. Results: Four patients carried mutations in diacylglycerol kinase-e, one p.H536Qfs*16 homozygote and three compound heterozygotes (p.W322*/p.P498R, two patients; p.Q248H/p.G484Gfs*10, one patient). Three patients also carried heterozygous mutations in thrombomodulin or C3. Extensive plasma infusions controlled atypical hemolytic uremic syndrome recurrences and prevented renal failure in the two patients with diacylglycerol kinase-e and thrombomodulin mutations. A positive response to plasma infusions and complement inhibition treatment was also observed in the patient with concurrent diacylglycerol kinase-« and C3 mutations. Conclusions: Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-e mutations and that treatments on the basis of plasma infusions and complement inhibition are potentially useful in patients with combined diacylglycerol kinase-e and complement mutations. A comprehensive understanding of the genetic component predisposing to atypical hemolytic uremic syndrome is, therefore, critical to guide an effective treatment. © 2014 by the American Society of Nephrology.

Corradini B.,University of Modena and Reggio Emilia | Sanchez-Diz P.,University of Santiago de Compostela | Sanchez-Diz P.,Research Center Biomedica en Enfermedades Raras | Alu M.,University of Modena and Reggio Emilia | And 4 more authors.
Forensic Science International: Genetics Supplement Series | Year: 2011

Large-scale population studies have proved that genetic factors contribute to individual differences in smoking behavior. Genes responsible for nicotine's pharmacokinetics and pharmacodynamics seem mainly involved, although a significant fraction of variance remains unexplained. In this study we examined 10 SNPs from 8 candidate genes with positive previous reports of association with smoking. A total of 454 Italian unrelated subjects were genotyped by a multiplex minisequencing assay through the SNaPShot kit. Cases were chosen as current and former nicotine dependent (FTND. ≥. 4 and SQ. ≥. 15), while controls were smoking-exposed but non-dependent and never smoker individuals (FTND = 0 and SQ ≤ 10 and FTND = 0 and SQ = 0, respectively). Preliminary results shows that the SNPs CHRNA5-rs16969968 and CHRNA3-rs1051730 could be associated with risk of developing nicotine dependence. Factors as age, sex, and exposition to smoke were also found as possible factors of risk of nicotine addiction. The identification of susceptibility loci for individual response to substance abuse is particularly motivating for medicine for the global epidemic dimension of addictions and the urgent need of effective preventive and therapeutic strategies. © 2011 Elsevier Ireland Ltd.

Jozsi M.,Eotvos Lorand University | Tortajada A.,CSIC - Biological Research Center | Tortajada A.,Research Center Biomedica en Enfermedades Raras | Uzonyi B.,Eotvos Lorand University | And 5 more authors.
Trends in Immunology | Year: 2015

Complement factor H-related proteins (FHRs) are strongly associated with different diseases involving complement dysregulation, which suggests a major role for these proteins regulating complement activation. Because FHRs are evolutionarily and structurally related to complement inhibitor factor H (FH), the initial assumption was that the FHRs are also negative complement regulators. Whereas weak complement inhibiting activities were originally reported for these molecules, recent developments indicate that FHRs may enhance complement activation, with important implications for the role of these proteins in health and disease. We review these findings here, and propose that FHRs represent a complex set of surface recognition molecules that, by competing with FH, provide improved discrimination of self and non-self surfaces and play a central role in determining appropriate activation of the complement pathway. © 2015 Elsevier Ltd.

Tortajada A.,CSIC - Biological Research Center | Tortajada A.,Research Center Biomedica en Enfermedades Raras | Yebenes H.,CSIC - Biological Research Center | Abarrategui-Garrido C.,Research Center Biomedica en Enfermedades Raras | And 21 more authors.
Journal of Clinical Investigation | Year: 2013

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. Copyright © 2013, American Society for Clinical Investigation.

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