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1.
Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene
Westra D Vernon KA Volokhina EB Pickering MC van de Kar NC van den Heuvel LP 《Journal of human genetics》2012,57(7):459-464
Atypical hemolytic uremic syndrome (aHUS) is a severe renal disorder that is associated with mutations in genes encoding proteins of the alternative complement pathway. Previously, we identified pathogenic variations in genes encoding complement regulators (CFH, CFI and MCP) in our aHUS cohort. In this study, we screened for mutations in the alternative pathway regulator CFHR5 in 65 aHUS patients by means of PCR on genomic DNA and sequence analysis. Potential pathogenicity of genetic alterations was determined by published data on CFHR5 variants, evolutionary conservation and in silico mutation prediction programs. Detection of serum CFHR5 was performed by western blot analysis and enzyme-linked immunosorbent assay. A potentially pathogenic sequence variation was found in CFHR5 in three patients (4.6%). All variations were located in short consensus repeats that might be involved in binding to C3b, heparin or C-reactive protein. The identified CFHR5 mutations require functional studies to determine their relevance to aHUS, but they might be candidates for an altered genetic profile predisposing to the disease. 相似文献
2.
Monteferrante G Brioschi S Caprioli J Pianetti G Bettinaglio P Bresin E Remuzzi G Noris M 《Molecular immunology》2007,44(7):1704-1708
Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (CD46) and complement factor I (CFI), were also involved in the pathogenesis of the disease. Anyway, mutations in the three genes account for no more than 50% of cases of non-Stx-HUS. Human complement factor H related 5 (CFHR5) is a recently characterised member of the human complement factor H (CFH) family that has been found as a component of immune deposits in human kidney with sclerotic lesions from different causes. CFHR5 possesses cofactor activity and has been proposed to play a role in complement regulation in the glomerulus. We screened CFHR5 gene for variations potentially involved in the aetiology of HUS. Forty-five patients with HUS and 80 controls were analysed. Altogether, 5 genetic variants in CFHR5 were found in overall 9/45 HUS patients and in 4/80 controls. Statistical analysis showed that allelic variants in CFHR5 were prefentially associated with HUS. Based on these data, we conclude that, though not causative, CFHR5 genetic alterations may play a secondary role in the pathogenesis of HUS. 相似文献
3.
Abrera-Abeleda MA Nishimura C Smith JL Sethi S McRae JL Murphy BF Silvestri G Skerka C Józsi M Zipfel PF Hageman GS Smith RJ 《Journal of medical genetics》2006,43(7):582-589
Introduction
Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.Subjects
Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded.Results
Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls.Conclusion
We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question. 相似文献4.
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Heinen S Sanchez-Corral P Jackson MS Strain L Goodship JA Kemp EJ Skerka C Jokiranta TS Meyers K Wagner E Robitaille P Esparza-Gordillo J Rodriguez de Cordoba S Zipfel PF Goodship TH 《Human mutation》2006,27(3):292-293
Many of the complement regulatory genes within the RCA cluster (1q32) have arisen through genomic duplication and the resulting high degree of sequence identity is likely to predispose to gene conversion events. The highest degree of identity is between the genes for factor H (CFH) and five factor H-related proteins--CFHL1, CFHL2, CFHL3, CFHL4, and CFHL5. CFH mutations are associated with atypical hemolytic uremic syndrome (aHUS). In the Newcastle cohort of 157 aHUS patients we have identified CFH mutations in 25 families or individuals. Eleven of these 25 independent mutations are either c.3226C>G,Q1076E; c.3572C>T,S1191L; c.3590T>C,V1197A or combined c.3572C>T,S1191L/c.3590T>C,V1197A. Sequence analysis shows that all four of these changes could have arisen as a result of gene conversion between CFH and CFHL1. Analysis of parental samples in two patients with S1191L/V1197A has shown that the changes are de novo thus providing conclusive evidence that gene conversion is the mutational mechanism in these two cases. To confirm that S1191L and V1197A are disease predisposing we examined their functional significance in three ways - analysis of the C3b/C3d binding characteristics of recombinant mutant S1191L/V1197A protein, heparin affinity chromatography and haemolytic assays of serum samples from aHUS patients carrying these changes. The results showed that these changes resulted in impaired C3b binding and a defective capacity to control complement activation on cellular surfaces. We, therefore, provide conclusive evidence that gene conversion is responsible for functionally significant CFH mutations in aHUS. 相似文献
7.
Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome 总被引:2,自引:0,他引:2
Kavanagh D Richards A Noris M Hauhart R Liszewski MK Karpman D Goodship JA Fremeaux-Bacchi V Remuzzi G Goodship TH Atkinson JP 《Molecular immunology》2008,45(1):95-105
Recent studies have identified mutations in the complement regulatory gene factor I (CFI) that predispose to atypical hemolytic uremic syndrome (aHUS). CFI is a two-chain serine protease in which the light chain carries the catalytic domain while the heavy chain's function is unclear. It downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (known as cofactor activity). Many CFI mutations in aHUS result in low CFI levels with a consequent quantitative defect in complement regulation. In others, the mutant protein is present in normal amounts but the presumed functional deficiency has not yet been defined. In this report we examine the nature of the functional defect in aHUS-associated CFI mutations. The I322T, D501N and D506V mutations reside in the serine protease domain of CFI and result in secreted proteins that lack C3b and C4b cofactor activity. The delTTCAC (1446-1450) mutant leads to a protein that is not secreted. The R299W mutant lies in a region of the CFI heavy chain of no known function. Our assessments demonstrate decreased C3b and C4b cofactor activity, providing evidence that this region is important for cofactor activity. In two other heavy chain mutants and one probable polymorphic variant, no functional deficiency was identified. These defective mutant proteins will result in an inability to appropriately control the complement cascade at sites of endothelial cell injury. The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS. 相似文献
8.
Syreeta DeCordova Amr Abdelgany Valarmathy Murugaiah Ansar A. Pathan Annapurna Nayak Tom Walker Abhishek Shastri Salman H. Alrokayan Haseeb A. Khan Shiv K. Singh Nick De Pennington Robert B. Sim Uday Kishore 《Immunobiology》2019,224(5):625-631
The complement system is an important humoral immune surveillance mechanism against tumours. However, many malignant tumours are resistant to complement mediated lysis. Here, we report secretion of complement factor H related protein 5 (FHR5) by primary tumour cells derived from Glioblastoma multiforme (GBM) patients. We investigated whether the secreted FHR5 exhibited functional activity similar to factor H, including inhibition of complement mediated lysis, acting as a co-factor for factor I mediated cleavage of C3b, and decay acceleration of C3 convertase. Immunoblotting analysis of primary GBM cells (B30, B31 and B33) supernatant showed the active secretion of FHR5, but not of Factor H. ELISA revealed that the secretion of soluble GBM-FHR5 by cultured GBM cells increased in a time-dependent manner. Primary GBM-FHR5 inhibited complement mediated lysis, possessed co-factor activity for factor I mediated cleavage and displayed decay acceleration of C3 convertase. In summary, we detected the secretion of FHR5 by primary GBM cells B30, B31 and B33. The results demonstrated that GBM-FHR5 shares biological function with FH as a mechanism primary GBM cells potentially use to resist complement mediated lysis. 相似文献
9.
Caprioli J Castelletti F Bucchioni S Bettinaglio P Bresin E Pianetti G Gamba S Brioschi S Daina E Remuzzi G Noris M;International Registry of Recurrent Familial HUS/TTP 《Human molecular genetics》2003,12(24):3385-3395
Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations. 相似文献
10.
In order to test the hypothesis that allelic variation withinthe Amyloid Precursor Protein (APP) gene influences susceptibilityto common forms of Alzheimer's disease (AD) we screened theentire coding, promoter and 3' untranslated sequences of theAPP gene for DNA variations in 30 unrelated patIents and eightcontrols with probable AD by a combination of RT-PCR, PCR andchemical cleavage mismatch analysis. Although we were unableto detect commonly occurring allelic variants, we were ableto detect a novel mutation within the APP gene in one individualwith late-onset AD. This mutation resulted in the substitutionof a tryptophan residue for an arginine residue at codon 328wIthin exon 7 which encodes the so-called protease Inhibitordomain of the 751 residue APP Isoform. However, the pathologicalsignificance of this mutation is uncertain as neither this,nor any other mutation occurring within exon 7 of the APP genewas found in any of a further 102 AD patients and 86 age-matchedcontrols. In conclusion, it is unlikely that susceptibilityto AD results from commonly occurring allelic variants of theAPP gene and it is even less probable that mutations withinexon 7 of the APP gene are important risk factors for late-onsetAD. 相似文献
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P. F. Mannaioni A. Pistelli F. Gambassi M. G. Di Bello S. Raspanti E. Masini 《Inflammation research》1991,33(1-2):57-60
The release of histamine from rat serosal mast cells induced by coincubation with resting and activated human platelets, or by exposure of mast cells to supernatants obtained from activated platelets, is significantly reduced by anti-free radical interventions, and is coupled with the generation of membrane lipid peroxidation products. These results suggest free radical participation in the activity of PDHRF. Human platelets possess specific binding sites for an H1-receptor antagonist, suggesting that H1-receptors could modulate the intracellular calcium levels in a pro-aggregatory fashion. 相似文献
14.
Robert L. Collins 《Behavior genetics》1970,1(2):99-109
Audiogenic seizure susceptibility to the initial presentation of intense sound was studied in generations of mice derived from the susceptible DBA/2J and the resistant C57BL/6J inbred strains. The experimental results led to the detection, location, and position of a new genetic locus affecting behavior in mice. The locus is designatedasp (audiogenic seizure prone), and the pattern of inheritance for high seizure risk is recessive. Evidence for the mapping ofasp results from the following experimental findings: (1) frequencies of seizures for each of six segregating generations obtained by crossing C57BL/6J and DBA/2J conformed to expectations based upon a single locus model of genetic inheritance; (2) theasp-locus is loosely linked to theb-locus and thus resides on Linkage Group VIII of the mouse; (3) linkage relationships betweenasp and other named mutations on LG VIII, pintail (Pt),misty (m), brown (b), and autosomal glucose-6-phosphate dehydrogenase (Gpd-1), indicate that the position of theasp-locus is towards the centromeric end of the chromosome. The order of loci isasp-b-Pt-Gpd-1; (4) no linkage was observed betweenasp and thed-locus of Linkage Group II. These experiments illustrate that new genetic loci, whose allelic alternatives exert major effects on chosen behavioral characters, can be identified and mapped in a directed search.In memory of Dr. Margaret M. Dickie who died July 4, 1969. Supported by NIH Research Grant MH 11327 from the National Institute of Mental Health and partly by an allocation from the American Cancer Society Institutional grant IN-19 to the Jackson Laboratory. The principles of laboratory animal care as advocated by the National Society for Medical Research are observed in this laboratory. 相似文献
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The oligonucleotide map of the whole RNA of A/swine/Hong Kong/3/76 (H3N2) virus showed a relationship to, but considerable differences from, the maps of human isolates of influenza A(H3N2) with which this isolate antigenically cross-reacted. Comparison of the individual oligonucleotide spots of whole virus RNAs confirmed previous results of antigenic analysis that A/swine/Hong Kong/3/76 virus was more similar to an early A/Hong Kong/68 virus than to later H3N2 viruses which circulated in man during 1976. On the other hand, another swine isolate, A/swine/Hong Kong/4/76, showed a quite similar oligonucleotide map to that of the contemporary prevalent A/Victoria/75-like viruses to which this strain was reported to be antigenically similar. Comparison of oligonucleotide maps of individual RNA segments indicated that all genes of the A/swine/Hong Kong/3/76 virus were derived from a human H3N2 virus. The findings provide biochemical evidence that A/swine/Hong Kong/3/76 virus represents a 1968 Hong Kong-like virus that underwent genetic mutation without extensive change of its antigenicity during maintenance in the swine population. 相似文献
17.
A factor in guinea-pig serum with accelerating effect on immune immobilization of Treponema pallidum (IAF): Isolation, purification and differentiation from the known haemolytic complement components and from lysozyme
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By consecutive euglobulin precipitation, gel filtration (Sephadex G-200/G-100), di-ethylaminoethyl (DEAE) and carboxy-methyl (CM 52) cellulose column chromatography a protein that has an enhancing effect on immune immobilization of Treponema pallidum was isolated from guinea-pig serum (Immobilization Accelerating Factor (IAF). The final isolation product was shown to be in a state of functional purity. IAF does not contain any of the known haemolytic complement subunits (C1—C9) or the muramidase lysozyme involved in immune immobilization of T. pallidum.
The sedimentation rate of IAF was estimated to be 8.1S. The approximate molecular weight was shown to be 150,000. The purified factor increased the number of immobilized treponemes in the modified Treponema pallidum immobilization test by more than 50 per cent.
相似文献18.
Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts 总被引:15,自引:0,他引:15
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Rimmelzwaan GF van Riel D Baars M Bestebroer TM van Amerongen G Fouchier RA Osterhaus AD Kuiken T 《The American journal of pathology》2006,168(1):176-183
The ongoing outbreak of avian influenza A virus (subtype H5N1) infection in Asia is of great concern because of the high human case fatality rate and the threat of a new influenza pandemic. Case reports in humans and felids suggest that this virus may have a different tissue tropism from other influenza viruses, which are normally restricted to the respiratory tract in mammals. To study its pathogenesis in a mammalian host, domestic cats were inoculated with H5N1 virus intratracheally (n = 3), by feeding on virus-infected chicks (n = 3), or by horizontal transmission (n = 2) and examined by virological and pathological assays. In all cats, virus replicated not only in the respiratory tract but also in multiple extra-respiratory tissues. Virus antigen expression in these tissues was associated with severe necrosis and inflammation 7 days after inoculation. In cats fed on virus-infected chicks only, virus-associated ganglioneuritis also occurred in the submucosal and myenteric plexi of the small intestine, suggesting direct infection from the intestinal lumen. All cats excreted virus not only via the respiratory tract but also via the digestive tract. This study in cats demonstrates that H5N1 virus infection causes systemic disease and spreads by potentially novel routes within and between mammalian hosts. 相似文献
19.
André F. Pastor Laís Rodrigues Moura José W.D. Neto Eduardo J.M. Nascimento Carlos E. Calzavara-Silva Ana Lisa V. Gomes Ana Maria da Silva Marli T. Cordeiro Ulisses Braga-Neto Sergio Crovella Laura H.V.G. Gil Ernesto T.A. Marques Jr. Bartolomeu Acioli-Santos 《Human immunology》2013
Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The −257T variant is located within a NF-κB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF-κB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral × all variant genotypes), as well as in individual genotypes comparison (ancestral × each variant genotype), where the most prevalent effect was observed in the CG/CG × CA/TG comparison. These findings support the involvement of −257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. 相似文献
20.
A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. 总被引:16,自引:0,他引:16
E Maestrini B P Korge J Oca?a-Sierra E Calzolari S Cambiaghi P M Scudder A Hovnanian A P Monaco C S Munro 《Human molecular genetics》1999,8(7):1237-1243
The multiplicity of functions served by intercellular gap junctions is reflected by the variety of phenotypes caused by mutations in the connexins of which they are composed. Mutations in the connexin26 (Cx26) gene ( GJB2 ) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3). We now report a Cx26 mutation in three families with mutilating keratoderma and deafness [Vohwinkel's syndrome (VS; MIM 124500), as originally described]. VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses and moderate degrees of deafness. In a large British pedigree, we have mapped the defect to the Cx26 locus. All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function. 相似文献