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1.
J Immunol ; 200(7): 2464-2478, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29500241

RESUMEN

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE, and THBD) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes CFH, CFI, CD46, C3, and DGKE than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in C3 and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of CFH In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/genética , Complemento C3/genética , Factor H de Complemento/genética , Vía Alternativa del Complemento/genética , Glomerulonefritis Membranoproliferativa/genética , Síndrome Hemolítico Urémico Atípico/patología , Complemento C3/metabolismo , Vía Alternativa del Complemento/fisiología , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Glomerulonefritis Membranoproliferativa/patología , Humanos , Masculino , Mutación Missense/genética
2.
Am J Hum Genet ; 97(2): 291-301, 2015 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-26235987

RESUMEN

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/genética , Genes Dominantes/genética , Músculo Liso/embriología , Mutación/genética , Proteínas de Dominio T Box/genética , Uréter/embriología , Sistema Urinario/anomalías , Secuencia de Bases , Ensayo de Cambio de Movilidad Electroforética , Exoma/genética , Células HEK293 , Humanos , Inmunohistoquímica , Inmunoprecipitación , Microscopía Fluorescente , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADN
3.
J Am Soc Nephrol ; 28(4): 1084-1091, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27974406

RESUMEN

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/complicaciones , Síndrome Hemolítico Urémico Atípico/genética , Proteínas de Microfilamentos/genética , Mutación , Microangiopatías Trombóticas/etiología , Adolescente , Niño , Femenino , Forminas , Humanos , Linaje
4.
Kidney Int ; 91(3): 539-551, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27989322

RESUMEN

In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/inmunología , Activación de Complemento , Complemento C3/inmunología , Glomerulonefritis/inmunología , Riñón/inmunología , Animales , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/genética , Síndrome Hemolítico Urémico Atípico/patología , Activación de Complemento/efectos de los fármacos , Complemento C3/genética , Inactivadores del Complemento/uso terapéutico , Predisposición Genética a la Enfermedad , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/genética , Glomerulonefritis/patología , Humanos , Riñón/efectos de los fármacos , Riñón/patología , Fenotipo , Factores de Riesgo , Resultado del Tratamiento
5.
J Am Soc Nephrol ; 27(6): 1617-24, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26490391

RESUMEN

The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/genética , Proteínas Sanguíneas/genética , Activación de Complemento/genética , Eliminación de Gen , Animales , Células Cultivadas , Factor H de Complemento/genética , Humanos , Ovinos
6.
J Am Soc Nephrol ; 26(4): 797-804, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25145936

RESUMEN

Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.


Asunto(s)
Glucuronidasa/genética , Sistema Urinario/fisiopatología , Enfermedades Urológicas/genética , Animales , Facies , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mutación , Enfermedades Urológicas/fisiopatología
7.
J Med Genet ; 51(11): 756-64, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25261570

RESUMEN

BACKGROUND: Inherited abnormalities of complement are found in ∼60% of patients with atypical haemolytic uraemic syndrome (aHUS). Such abnormalities are not fully penetrant. In this study, we have estimated the penetrance of the disease in three families with a CFH mutation (c.3643C>G; p. Arg1215Gly) in whom a common lineage is probable. 25 individuals have been affected with aHUS with three peaks of incidence-early childhood (n=6), early adulthood (n=11) and late adulthood (n=8). Eighteen individuals who have not developed aHUS carry the mutation. METHODS: We estimated penetrance at the ages of 4, 27, 60 and 70 years as both a binary and a survival trait using MLINK and Mendel. We genotyped susceptibility factors in CFH, CD46 and CFHR1 in affected and unaffected carriers. RESULTS AND CONCLUSIONS: We found that the estimates of penetrance at the age of 4 years ranged from <0.01 to 0.10, at the age of 27 years from 0.16 to 0.29, at the age of 60 years from 0.39 to 0.51 and at the age of 70 years from 0.44 to 0.64. We found that the CFH haplotype on the allele not carrying the CFH mutation had a significant effect on disease penetrance. In this family, we did not find that the CD46 haplotypes had a significant effect on penetrance.


Asunto(s)
Síndrome Hemolítico Urémico Atípico/genética , Penetrancia , Adulto , Anciano , Preescolar , Factor H de Complemento/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje
8.
J Am Soc Nephrol ; 25(11): 2425-33, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24722444

RESUMEN

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.


Asunto(s)
Factor H de Complemento/deficiencia , Factor H de Complemento/genética , Vía Alternativa del Complemento/genética , Eritrocitos/inmunología , Glomerulonefritis Membranoproliferativa/genética , Glomerulonefritis Membranoproliferativa/inmunología , Enfermedades Renales/genética , Animales , Factor H de Complemento/química , Factor H de Complemento/inmunología , Vía Alternativa del Complemento/inmunología , Cristalografía por Rayos X , Eritrocitos/citología , Salud de la Familia , Femenino , Haplotipos , Enfermedades por Deficiencia de Complemento Hereditario , Heterocigoto , Humanos , Enfermedades Renales/inmunología , Masculino , Linaje , Polimorfismo Genético , Estructura Terciaria de Proteína , Ovinos , Relación Estructura-Actividad
9.
Blood ; 119(2): 591-601, 2012 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-22058112

RESUMEN

Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomology-mediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule.


Asunto(s)
Apolipoproteínas/genética , Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Factor H de Complemento/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad , Síndrome Hemolítico-Urémico/genética , Animales , Apolipoproteínas/metabolismo , Síndrome Hemolítico Urémico Atípico , Autoanticuerpos , Secuencia de Bases , Proteínas Sanguíneas/metabolismo , Western Blotting , Activación de Complemento , Proteínas Inactivadoras del Complemento C3b/metabolismo , Factor H de Complemento/metabolismo , Eritrocitos/metabolismo , Hemólisis , Síndrome Hemolítico-Urémico/metabolismo , Síndrome Hemolítico-Urémico/patología , Recombinación Homóloga , Humanos , Datos de Secuencia Molecular , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Mutación/genética , Linaje , Homología de Secuencia de Ácido Nucleico , Ovinos , Resonancia por Plasmón de Superficie
10.
J Am Soc Nephrol ; 24(3): 475-86, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23431077

RESUMEN

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.


Asunto(s)
Proteínas del Sistema Complemento/genética , Síndrome Hemolítico-Urémico/genética , Síndrome Hemolítico-Urémico/inmunología , Mutación , Adulto , Síndrome Hemolítico Urémico Atípico , Niño , Preescolar , Complemento C3/genética , Factor B del Complemento/genética , Factor H de Complemento/genética , Femenino , Fibrinógeno/genética , Estudios de Asociación Genética , Haplotipos , Humanos , Lactante , Masculino , Proteína Cofactora de Membrana/genética , Persona de Mediana Edad , Linaje , Penetrancia , Factores de Riesgo , Adulto Joven
11.
J Exp Med ; 204(6): 1245-8, 2007 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-17548524

RESUMEN

Immune recognition is coupled to powerful proinflammatory effector pathways that must be tightly regulated. The ancient alternative pathway of complement activation is one such proinflammatory pathway. Genetic susceptibility factors have been identified in both regulators and activating components of the alternative pathway that are associated with thrombotic microangiopathies, glomerulonephritides, and chronic conditions featuring debris deposition. These observations indicate that excessive alternative pathway activation promotes thrombosis in the microvasculature and tissue damage during debris accumulation. Intriguingly, distinct genetic changes in factor H (FH), a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (dense deposit disease), or age-related macular degeneration (AMD). A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders.


Asunto(s)
Vía Alternativa del Complemento/inmunología , Modelos Animales de Enfermedad , Síndrome Hemolítico-Urémico/genética , Degeneración Macular/genética , Modelos Inmunológicos , Animales , Factor H de Complemento/genética , Factor H de Complemento/inmunología , Síndrome Hemolítico-Urémico/inmunología , Humanos , Degeneración Macular/inmunología , Ratones
12.
Am J Kidney Dis ; 62(5): 978-83, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23870792

RESUMEN

We report a male infant who presented at 8 months of age with atypical hemolytic uremic syndrome (aHUS) responsive to plasma therapy. Investigation showed him to have complement factor H (CFH) deficiency associated with a homozygous CFH mutation (c.2880delT [p.Phe960fs]). Mutation screening of the child's parents revealed that the father was heterozygous for this change but that it was not present in his mother. Chromosome 1 uniparental isodisomy of paternal origin was confirmed by genotyping chromosome 1 SNPs. CD46 SNP genotyping was undertaken in this individual and another patient with CFH deficiency associated with chromosome 1 uniparental isodisomy. This showed a homozygous aHUS risk haplotype (CD46GGAAC) in the patient with aHUS and a homozygous glomerulonephritis risk haplotype (CD46AAGGT) in the patient with endocapillary glomerulonephritis. We also showed that FHL-1 (factor H-like protein 1) was present in the patient with aHUS and absent in the patient with glomerulonephritis. This study emphasizes that modifiers such as CD46 and FHL-1 may determine the kidney phenotype of patients who present with homozygous CFH deficiency.


Asunto(s)
Factor H de Complemento/deficiencia , Genotipo , Síndrome Hemolítico-Urémico/genética , Enfermedades Renales/genética , Fenotipo , Disomía Uniparental/genética , Síndrome Hemolítico Urémico Atípico , Factor H de Complemento/genética , Haplotipos/genética , Enfermedades por Deficiencia de Complemento Hereditario , Homocigoto , Humanos , Lactante , Masculino , Proteína Cofactora de Membrana/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética
13.
Blood ; 115(2): 379-87, 2010 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-19861685

RESUMEN

Factor H autoantibodies have been reported in approximately 10% of patients with atypical hemolytic uremic syndrome (aHUS) and are associated with deficiency of factor H-related proteins 1 and 3. In this study we examined the prevalence of factor H autoantibodies in the Newcastle cohort of aHUS patients, determined whether the presence of such autoantibodies is always associated with deficiency of factor H-related proteins 1 and 3, and examined whether such patients have additional susceptibility factors and/or mutations in the genes encoding complement regulator/activators. We screened 142 patients with aHUS and found factor H autoantibodies in 13 individuals (age 1-11 years). The presence of the autoantibodies was confirmed by Western blotting. By using multiplex ligation-dependent probe amplification we measured complement factor H-related (CFHR)1 and CFHR3 copy number. In 10 of the 13 patients there were 0 copies of CFHR1, and in 3 patients there were 2. In 3 of the patients with 0 copies of CFHR1 there was 1 copy of CFHR3, and these individuals exhibited a novel deletion incorporating CFHR1 and CFHR4. In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation.


Asunto(s)
Apolipoproteínas/genética , Autoanticuerpos/sangre , Proteínas Sanguíneas/genética , Complemento C3/genética , Proteínas Inactivadoras del Complemento C3b/genética , Factor H de Complemento/genética , Factor I de Complemento/genética , Síndrome Hemolítico-Urémico/sangre , Síndrome Hemolítico-Urémico/genética , Proteína Cofactora de Membrana/genética , Apolipoproteínas/inmunología , Apolipoproteínas/metabolismo , Autoanticuerpos/inmunología , Proteínas Sanguíneas/inmunología , Proteínas Sanguíneas/metabolismo , Niño , Preescolar , Estudios de Cohortes , Complemento C3/inmunología , Complemento C3/metabolismo , Proteínas Inactivadoras del Complemento C3b/inmunología , Proteínas Inactivadoras del Complemento C3b/metabolismo , Factor H de Complemento/inmunología , Factor H de Complemento/metabolismo , Factor I de Complemento/inmunología , Factor I de Complemento/metabolismo , Femenino , Dosificación de Gen , Síndrome Hemolítico-Urémico/inmunología , Humanos , Lactante , Masculino , Proteína Cofactora de Membrana/inmunología , Proteína Cofactora de Membrana/metabolismo , Eliminación de Secuencia
14.
J Am Soc Nephrol ; 21(1): 113-23, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19959718

RESUMEN

Primary vesicoureteric reflux accounts for approximately 10% of kidney failure requiring dialysis or transplantation, and sibling studies suggest a large genetic component. Here, we report a whole-genome linkage and association scan in primary, nonsyndromic vesicoureteric reflux and reflux nephropathy. We used linkage and family-based association approaches to analyze 320 white families (661 affected individuals, generally from families with two affected siblings) from two populations (United Kingdom and Slovenian). We found modest evidence of linkage but no clear overlap with previous studies. We tested for but did not detect association with six candidate genes (AGTR2, HNF1B, PAX2, RET, ROBO2, and UPK3A). Family-based analysis detected associations with one single-nucleotide polymorphism (SNP) in the UK families, with three SNPs in the Slovenian families, and with three SNPs in the combined families. A case-control analysis detected associations with three additional SNPs. The results of this study, which is the largest to date investigating the genetics of reflux, suggest that major loci may not exist for this common renal tract malformation within European populations.


Asunto(s)
Ligamiento Genético/genética , Reflujo Vesicoureteral/etnología , Reflujo Vesicoureteral/genética , Estudios de Casos y Controles , Interpretación Estadística de Datos , Factor Nuclear 1-beta del Hepatocito/genética , Humanos , Modelos Logísticos , Glicoproteínas de Membrana/genética , Factor de Transcripción PAX2/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas c-ret/genética , Receptor de Angiotensina Tipo 2/genética , Receptores Inmunológicos/genética , Hermanos , Eslovenia , Reino Unido , Uroplaquina III
15.
Curr Opin Hematol ; 17(5): 432-8, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20613506

RESUMEN

PURPOSE OF REVIEW: The last few years revealed a molecular distinction between thrombotic thrombocytopenic purpura, a disease characterized by a lack of ADAMTS13 activity, and atypical hemolytic uremic syndrome (aHUS), a disease of complement overactivation. Many different predisposing genetic factors resulting in complement overactivation have been described in aHUS. Additionally, autoantibodies against complement regulatory proteins have been reported. RECENT FINDINGS: The last year has seen the description of a new risk factor for aHUS in the form of mutations in thrombomodulin. As with other genetic risk factors seen in aHUS, these mutations result in impaired regulation of complement. It is increasingly recognized that a confluence of risk factors resulting in complement overactivation may be required for the disease to manifest. In the last year the complement inhibitor eculizumab has been used successfully to treat patients with aHUS. SUMMARY: The characterization of the molecular defect in aHUS has allowed targeted therapy to be used. Although early reports of the efficacy of the complement inhibitor eculizumab are promising, the outcome of a recent clinical trial is awaited.


Asunto(s)
Activación de Complemento/inmunología , Síndrome Hemolítico-Urémico/genética , Síndrome Hemolítico-Urémico/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Autoanticuerpos , Activación de Complemento/genética , Factor H de Complemento/deficiencia , Factor H de Complemento/genética , Inactivadores del Complemento/uso terapéutico , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Humanos , Intercambio Plasmático , Trombofilia
16.
Clin J Am Soc Nephrol ; 16(11): 1639-1651, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34551983

RESUMEN

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.


Asunto(s)
Autoanticuerpos/sangre , Complemento C3/metabolismo , Glomerulonefritis Membranoproliferativa/sangre , Glomerulonefritis Membranoproliferativa/etiología , Fenotipo , Adolescente , Niño , Preescolar , Complemento C3/genética , Complemento C3b/inmunología , Complemento C4/metabolismo , Factor B del Complemento/inmunología , Factor H de Complemento/inmunología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/terapia , Supervivencia de Injerto , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Masculino , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Recurrencia , Sistema de Registros , Factores de Riesgo
17.
Blood ; 112(13): 4948-52, 2008 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-18796626

RESUMEN

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.


Asunto(s)
Complemento C3/genética , Síndrome Hemolítico-Urémico/genética , Mutación , Adolescente , Adulto , Niño , Preescolar , Codón sin Sentido , Complemento C3/análisis , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Síndrome Hemolítico-Urémico/etiología , Síndrome Hemolítico-Urémico/inmunología , Heterocigoto , Humanos , Lactante , Mutación Missense , Adulto Joven
18.
Nephrol Dial Transplant ; 25(10): 3421-5, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20530807

RESUMEN

BACKGROUND: A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years. RESULTS: Stenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation. CONCLUSION: Arterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.


Asunto(s)
Arteriopatías Oclusivas/etiología , Factor B del Complemento/genética , Síndrome Hemolítico-Urémico/complicaciones , Mutación , Adolescente , Femenino , Humanos , Terapia de Reemplazo Renal/efectos adversos
19.
PLoS Genet ; 3(3): e41, 2007 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-17367211

RESUMEN

Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of approximately 84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.


Asunto(s)
Proteínas Sanguíneas/genética , Proteínas Inactivadoras del Complemento C3b/genética , Factor H de Complemento/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad , Síndrome Hemolítico-Urémico/genética , Adolescente , Adulto , Secuencia de Bases , Proteínas Sanguíneas/deficiencia , Estudios de Casos y Controles , Cromosomas Humanos/genética , Proteínas Inactivadoras del Complemento C3b/deficiencia , Factor H de Complemento/deficiencia , Exones/genética , Dosificación de Gen , Frecuencia de los Genes , Reordenamiento Génico , Humanos , Datos de Secuencia Molecular , Familia de Multigenes
20.
Ren Fail ; 32(6): 753-6, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20540647

RESUMEN

We report a case of atypical hemolytic uremic syndrome (aHUS) triggered by influenza A (H1N1) in a 17-year-old boy with a mutation in the gene (CD46) encoding the transmembrane complement regulator membrane cofactor protein. The patient recovered completely following treatment with oseltamivir, plasma exchange, and hemodialysis. We describe the case and discuss this unusual association of diseases.


Asunto(s)
Síndrome Hemolítico-Urémico/virología , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/complicaciones , Adolescente , Humanos , Masculino
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