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1.
Eur J Pediatr ; 181(5): 1997-2004, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35118517

RESUMO

Diagnosis of primary complement deficiencies requires a high index of suspicion. Thus, susceptible patients are often underdiagnosed and untreated. Here, we present a multicenter experience with two novel inborn errors of the classical complement system. This is a retrospective multicenter analysis of computerized medical records of children (<18 years) admitted in the period between 2012 and 2018 at Shaare Zedek Medical Center in Jerusalem and Edmond and Lily Safra Children's Hospital, Tel-Hashomer Medical Center, in Ramat Gan, Israel. Patients were genetically diagnosed by a complementary immune workup. We identified 5 patients (3 males) from four different families harboring two novel mutations in the complement components C6-C8. Genetic mutations were identified by whole-exome sequencing or by sequencing of the coding exons of a single gene based on the findings in the immune workup. Clinical manifestations consisted of meningitis with or without meningococcemia. The immune workup demonstrated nearly absent levels of CH50, compatible with a complement pathway defect. Diagnosis delay ranged between 0 and 30 years. CONCLUSION: Awareness of risk factors for primary complement deficiencies, even at the first infectious episode, should facilitate prompt immune and genetic workup, commencing diagnosis and proper treatment for the patient and family. WHAT IS KNOWN: • Deficiencies in the classical terminal complement components increase susceptibility to invasive meningococcal infections. • Recurrent meningococcal infections mandate a diagnostic workup of the complement system. WHAT IS NEW: • Genetic workup can be utilized for prompt diagnosis of complement deficiencies. • High rates of consanguinity, even in the presence of a single meningococcal infection, should promote immune and genetic workups.


Assuntos
Meningite Meningocócica , Infecções Meningocócicas , Neisseria meningitidis , Criança , Complemento C6 , Complemento C8/genética , Proteínas do Sistema Complemento/genética , Feminino , Doenças da Deficiência Hereditária de Complemento , Humanos , Masculino , Estudos Retrospectivos
2.
J Clin Immunol ; 42(3): 665-671, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35084692

RESUMO

BACKGROUND: Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies. METHODS: Clinicians from seven UK centers provided anonymised demographic, clinical, and laboratory data on patients with terminal complement deficiencies, which were collated and analysed. RESULTS: Forty patients, median age 19 (range 3-62) years, were identified with terminal complement deficiencies. Ten (62%) of 16 patients with low serum C5 concentrations had underlying pathogenic CFH or CFI gene variants. Two-thirds were from consanguineous Asian families, and 80% had an affected family member. The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections. Nine (22%) were treated in intensive care for meningococcal septicaemia. Two patients had died, one from intercurrent COVID-19. Twenty-one (52%) were asymptomatic and diagnosed based on family history. All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics. DISCUSSION: The genetic etiology and clinical course of patients with primary and secondary terminal complement deficiency are variable. Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important. Only half of the patients develop septicaemia, but all should have a clear management plan.


Assuntos
COVID-19 , Infecções Meningocócicas , Sepse , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Proteínas do Sistema Complemento/genética , Doenças da Deficiência Hereditária de Complemento , Humanos , Infecções Meningocócicas/genética , Pessoa de Meia-Idade , Reino Unido/epidemiologia , Adulto Jovem
4.
Exp Biol Med (Maywood) ; 247(2): 77-86, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34775843

RESUMO

Age-related macular degeneration is the leading cause of blindness in the elderly. The Y402H polymorphism in complement factor H promotes disease-like pathogenesis, and a Cfh+/- murine model can replicate this phenotype, but only after two years. We reasoned that by combining CFH deficiency with cigarette smoke exposure, we might be able to accelerate disease progression to facilitate preclinical research in this disease. Wild-type and Cfh+/- mice were exposed to nose-only cigarette smoke for three months. Retinal tissue morphology and visual function were evaluated by optical coherence tomography, fundus photography and autofluorescence, and electroretinogram. Retinal pigment epithelial cell phenotype and ultrastructure were evaluated by immunofluorescence staining and transmission electron microscopy. Cfh+/- smoking mice showed a dome-like protruding lesion at the ellipsoid zone (drusen-like deposition), many retinal hyper-autofluorescence spots, and a marked decrease in A- and B-wave amplitudes. Compared with non-smoking mice, wild-type and Cfh+/- smoking mice showed sub-retinal pigment epithelium complement protein 3 deposition, activation of microglia, metabolic waste accumulation, and impairment of tight junctions. Microglia cells migrated into the photoreceptor outer segment layer in Cfh+/- smoking mice showed increased activation. Our results suggest that exposing Cfh+/- mice to smoking leads to earlier onset of age-related macular degeneration than in other animal models, which may facilitate preclinical research into the pathophysiology and treatment of this disease.


Assuntos
Fator H do Complemento/deficiência , Doenças da Deficiência Hereditária de Complemento/metabolismo , Nefropatias/metabolismo , Degeneração Macular/metabolismo , Fumar/metabolismo , Animais , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Modelos Animais de Doenças , Doenças da Deficiência Hereditária de Complemento/genética , Nefropatias/genética , Degeneração Macular/etiologia , Degeneração Macular/genética , Camundongos , Camundongos Knockout , Fumar/efeitos adversos , Fumar/genética
5.
J Infect Chemother ; 28(2): 308-310, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34736815

RESUMO

Gonococcal infection is rarely associated with septic shock. We describe a recurrent case of septic shock related to disseminated gonococcemia in a patient with systemic lupus erythematosus and hypocomplementemic urticarial vasculitis, and discuss the implication of profound acquired complement deficiency secondary to these auto-immune diseases. This case raises the question of systematic antibioprophylaxis in patients with acquired complement deficiency.


Assuntos
Lúpus Eritematoso Sistêmico , Urticária , Vasculite , Proteínas do Sistema Complemento , Doenças da Deficiência Hereditária de Complemento , Humanos , Lúpus Eritematoso Sistêmico/complicações , Urticária/etiologia
8.
Medicine (Baltimore) ; 100(13): e25265, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787610

RESUMO

RATIONALE: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants. PATIENT CONCERNS: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger. DIAGNOSIS: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test. INTERVENTIONS: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants. OUTCOMES: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela. LESSONS: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.


Assuntos
Complemento C7/deficiência , Variação Genética/genética , Gonorreia/genética , Doenças da Deficiência Hereditária de Complemento/genética , Doenças da Deficiência Hereditária de Complemento/microbiologia , Neisseria gonorrhoeae , Complemento C7/genética , Feminino , Gonorreia/microbiologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade
10.
Dermatol Ther ; 34(1): e14510, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166012

RESUMO

Leiner's disease (LD) is a rare and serious syndrome of infantile erythroderma of severe and progressive generalized seborrheic-like dermatitis, recalcitrant diarrhea, malabsorption and wasting, and recurrent local and systemic infections. The purpose of this study is to provide an updated review on management with a summarized review of available peer-reviewed articles on LD. The mechanisms underlying this disease process remain unclear. The diagnosis includes demonstration of deficient opsonic activity along with the clinical tetrad of erythroderma, persistent gastrointestinal disturbance, superimposed bacterial or candidal infection, and marked wasting. An important correlation between LD and defective yeast and Staphylococcus aureus opsonization has been established. For the familial form of LD, an association of either complement three deficiency or complement five dysfunction has been made. LD should be distinguished from other types of infantile erythroderma, including Omenn syndrome. Treatment includes fluid and nutrition replacement, antibiotics to control infection, and fresh-frozen plasma therapy. The prognosis is unclear; it depends on treatment. LD is a life-threatening condition that requires prompt identification and hospitalization. Affected infants who receive vigorous treatment not only have the prospect of surviving, but also generally lead a normal life after infancy.


Assuntos
Complemento C5/deficiência , Dermatite Esfoliativa , Doenças da Deficiência Hereditária de Complemento , Antibacterianos/uso terapêutico , Dermatite Esfoliativa/diagnóstico , Dermatite Esfoliativa/etiologia , Dermatite Esfoliativa/terapia , Doenças da Deficiência Hereditária de Complemento/diagnóstico , Doenças da Deficiência Hereditária de Complemento/etiologia , Doenças da Deficiência Hereditária de Complemento/terapia , Humanos , Lactente
11.
Vnitr Lek ; 66(6): 346-352, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33380138

RESUMO

Complement system plays a crucial role in innate imunity. Complement deficiencies are often associated with severe infections, usually meningoccocal, pneumococcal or caused by Haemophilus influenzae, or with autoimmune diseases, especially systemic lupus erythematodes. Inherited complement deficiencies are very rare although their prevalence in population may be underestimated due to lower availability of adequate laboratory testing. Acquired complement deficiencies accompany other underlying diseases and often are caused by increased consumption and only partial.


Assuntos
Doenças Autoimunes , Doenças da Deficiência Hereditária de Complemento , Ativação do Complemento , Proteínas do Sistema Complemento , Humanos
12.
Sci Rep ; 10(1): 19500, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177623

RESUMO

Historically, the membrane attack complex, composed of complement components C5b-9, has been connected to lytic cell death and implicated in secondary injury after a CNS insult. However, studies to date have utilized either non-littermate control rat models, or mouse models that lack significant C5b-9 activity. To investigate what role C5b-9 plays in spinal cord injury and recovery, we generated littermate PVG C6 wildtype and deficient rats and tested functional and histological recovery after moderate contusion injury using the Infinite Horizon Impactor. We compare the effect of C6 deficiency on recovery of locomotor function and histological injury parameters in PVG rats under two conditions: (1) animals maintained as separate C6 WT and C6-D homozygous colonies; and (2) establishment of a heterozygous colony to generate C6 WT and C6-D littermate controls. The results suggest that maintenance of separate homozygous colonies is inadequate for testing the effect of C6 deficiency on locomotor and histological recovery after SCI, and highlight the importance of using littermate controls in studies involving genetic manipulation of the complement cascade.


Assuntos
Complemento C6/deficiência , Doenças da Deficiência Hereditária de Complemento/complicações , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Comportamento Animal , Complemento C6/genética , Complexo de Ataque à Membrana do Sistema Complemento/genética , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Feminino , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Substância Cinzenta/citologia , Substância Cinzenta/metabolismo , Doenças da Deficiência Hereditária de Complemento/genética , Heterozigoto , Locomoção , Masculino , Proteína Básica da Mielina/metabolismo , Ratos Mutantes , Seleção Artificial , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/genética , Vértebras Torácicas/lesões , Substância Branca/citologia , Substância Branca/metabolismo
13.
Sci Rep ; 10(1): 17593, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067533

RESUMO

Excessive intake of fat causes accumulation of fat in liver, leading to non-alcoholic fatty liver disease (NAFLD). High-fat diet (HFD) upregulates the expression of Factor D, a complement pathway component, in the liver of mice. However, the functions of Factor D in liver are not well known. Therefore, the current study investigated the relationship between Factor D and hepatic lipid accumulation using CRISPR/Cas9-mediated Factor D knockout (FD-KO) mice. Factor D deficiency downregulated expression of genes related to fatty acid uptake and de novo lipogenesis in the liver. Furthermore, Factor D deficiency reduced the expression of inflammatory factors (Tnf and Ccl2) and fibrosis markers and decreased accumulation of F4/80-positive macrophages. These data suggest that the Factor D deficiency improved hepatic lipid accumulation and hepatic inflammation in HFD-fed mice.


Assuntos
Fator D do Complemento/deficiência , Fator D do Complemento/metabolismo , Doenças da Deficiência Hereditária de Complemento/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Animais , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Doenças da Deficiência Hereditária de Complemento/metabolismo , Inflamação/metabolismo , Resistência à Insulina/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
14.
Vnitr Lek ; 66(2): 87-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32942894

RESUMO

C2 deficiency represents the most frequent type of a complement deficiency. Clinical manifestation includes infections caused by encapsulated bacteria (Steptococcus pneumoniae, Neisseria meningitidis) such as meningitis, gonitis, pneumonia or septicaemia. A causative treatment has not been available yet. A prophylactic vaccination and/or a long-term antibiotics prophylaxis are recommended. Here we report 2 patients from 2 unrelated families. The first patient suffered from recurrent otitis in his childhood. He underwent osteomyelitis, meningitis complicates with hear-loss, and one episode of pneumonia during adulthood. The second index patient underwent uncomplicated meningitis in his preschool age. He has been treated for recurrent upper-airways infections later. His sister has been completely asymptomatic. The deletion 28 bp (c.841-849+19del28) in C2-gene was detected in all of them in homozygous form. Our paper highlights the variability of a clinical manifestation in homozygous carriers, ranged from asymptomatic cases to patients with history of severe complications. The diagnosis is frequently made even in adulthood.


Assuntos
Doenças da Deficiência Hereditária de Complemento , Pneumonia , Sepse , Adulto , Antibioticoprofilaxia , Criança , Pré-Escolar , Humanos , Masculino , Vacinação
15.
Pediatr Rheumatol Online J ; 18(1): 74, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32972440

RESUMO

BACKGROUND: Acquired complement deficiency can occur in the setting of autoimmune syndromes, such as systemic lupus erythematosus (SLE), with very low or, occasionally, undetectable C3 levels. Based on inherited complement defects, patients with transiently low complement may be at similar risk for serious bacterial infection, but the degree of risk related to C3 level and temporal association is unknown. METHODS: We performed a retrospective study including pediatric patients with undetectable total complement activity or absent individual complement components measured at our institution from 2002 to 2018. We assessed annual rate of serious bacterial infection (SBI) defined as requiring hospitalization and/or parenteral antibiotics by manual chart review. Among included SLE patients, we assessed the 30-day probability of SBI for given C3 measurements using a logistic regression model to determine risk. Primary complement deficiency was analyzed for SBI rate as comparison. Covariates included age, level of immune suppression and history of lupus nephritis. RESULTS: Acquired complement deficiency secondary to SLE-related disease [n = 44] was the most common underlying diagnosis associated with depressed complement levels and were compared to a cohort of primary complement deficient patients [n = 18]. SBI per 100 person-years and cohort demographics were described in parallel. Our logistic regression analysis of pediatric patients with SLE showed low C3 level was temporally associated with having an SBI event. Given equivalent immunosuppression, patients with an SBI had lower C3 levels at the beginning of the observation period relative to patients without SBI. CONCLUSION: Pediatric patients with the diagnosis of SLE can develop very low C3 levels that associate with risk of serious bacterial infection comparable to that of patients with primary complement deficiency. Patients prone to severe complement consumption may particularly be at risk.


Assuntos
Infecções Bacterianas/epidemiologia , Complemento C3/deficiência , Doenças da Deficiência Hereditária de Complemento/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Administração Intravenosa , Adolescente , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Complemento C3/imunologia , Feminino , Doenças da Deficiência Hereditária de Complemento/imunologia , Hospitalização/estatística & dados numéricos , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/imunologia , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença
16.
Allergy Asthma Proc ; 41(5): 386-388, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32867893

RESUMO

Background: Terminal complement component deficiencies are risk factors for neisserial infections. Objective: To review the clinical characteristics, the diagnosis and the management of patients with a terminal complement component deficiency. Methods: Pertinent articles were selected and reviewed in relation to a case presentation of C6 deficiency. Results: A case of a 56-year old patient with a history of meningitis, chronic rash, and C6 deficiency was presented, followed by discussion of clinical characteristics, diagnosis, and management of terminal complement component deficiencies. Clinical pearls and pitfalls were reviewed for the practicing allergist/immunologist and fellow-in-training. Conclusion: C6 deficiency is the most common terminal complement component deficiency and can present later in age with N. meningitidis infections. Patients can be screened for terminal complement component deficiency by checking CH50.


Assuntos
Envelhecimento/fisiologia , Complemento C6/deficiência , Complemento C6/genética , Doenças da Deficiência Hereditária de Complemento/diagnóstico , Meningite Meningocócica/diagnóstico , Vacinas Meningocócicas/imunologia , Neisseria meningitidis/fisiologia , Antibioticoprofilaxia , Ensaio de Atividade Hemolítica de Complemento , Feminino , Fibronectinas/análise , Doenças da Deficiência Hereditária de Complemento/complicações , Humanos , Meningite Meningocócica/etiologia , Meningite Meningocócica/prevenção & controle , Pessoa de Meia-Idade , Proteínas Recombinantes/análise
17.
Nat Med ; 26(10): 1609-1615, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32747830

RESUMO

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral-host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality-effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.


Assuntos
Ativação do Complemento/imunologia , Infecções por Coronavirus/mortalidade , Hemorragia/epidemiologia , Degeneração Macular/epidemiologia , Pneumonia Viral/mortalidade , Trombocitopenia/epidemiologia , Trombose/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/epidemiologia , COVID-19 , Ativação do Complemento/genética , Infecções por Coronavirus/sangue , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Expressão Gênica , Hemorragia/sangue , Hemorragia/imunologia , Doenças da Deficiência Hereditária de Complemento/epidemiologia , Doenças da Deficiência Hereditária de Complemento/imunologia , Humanos , Hipertensão/epidemiologia , Intubação Intratraqueal , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Obesidade/epidemiologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Modelos de Riscos Proporcionais , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Trombocitopenia/sangue , Trombose/sangue
19.
Clin Exp Immunol ; 202(3): 379-383, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32640035

RESUMO

Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement-mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation.


Assuntos
Complemento C3/deficiência , Doenças da Deficiência Hereditária de Complemento/imunologia , Peritonite/imunologia , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Complemento C3/imunologia , Feminino , Doenças da Deficiência Hereditária de Complemento/patologia , Humanos , Peritonite/patologia , Infecções Pneumocócicas/patologia
20.
Adv Chronic Kidney Dis ; 27(2): 120-127.e4, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32553244

RESUMO

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with loss of regulation of the alternative pathway of complement and its resulting overactivation. As rare diseases, genetic variants leading to aHUS and C3G were previously analysed in relatively low patient numbers. To improve this analysis, data were pooled from six centres. Totals of 610 rare variants for aHUS and 82 for C3G were presented in an interactive database for 13 genes. Using allele frequency comparisons with the Exome Aggregation Consortium as a reference genome, the patients with aHUS showed significantly more protein-altering ultrarare variants (allele frequency <0.01%) in five genes CFH, CFI, CD46, C3, and DGKE. In patients with C3G, the corresponding association was only found for C3 and CFH. Protein structure analyses of these five proteins showed distinct differences in the positioning of these variants in C3 and FH. For aHUS, variants were clustered at the C-terminus of FH and implicated changes in the binding of FH to host cell surfaces. For C3G, variants were clustered at the N-terminal C3b binding site of FH and implicated changes in the fluid-phase regulation of C3b. We discuss the utility of the Web database as a patient resource for clinicians.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Complemento C3/genética , Síndrome Hemolítico-Urêmica Atípica/genética , Síndrome Hemolítico-Urêmica Atípica/imunologia , Síndrome Hemolítico-Urêmica Atípica/fisiopatologia , Frequência do Gene , Predisposição Genética para Doença , Doenças da Deficiência Hereditária de Complemento/diagnóstico , Doenças da Deficiência Hereditária de Complemento/imunologia , Humanos , Mutação
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