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1.
Milman N Andersen CB Hansen A van Overeem Hansen T Nielsen FC Fledelius H Ahrens P Nielsen OH 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2006,114(12):912-919
Blau syndrome is a hereditary granulomatous disease caused by mutations in the CARD15 gene that is diagnosed in children of young age with exanthema/erythema, arthritis/periarthritis and/or uveitis. We report two cases of Blau syndrome in Danish Caucasian monozygotic male twins, exhibiting a heterozygous de novo R334W mutation in codon 334 of CARD15. The patients were initially diagnosed as having sarcoidosis. In both twins, symptoms (exanthema, arthritis/periarthritis) started at 1 year of age, and were followed by uveitis at 7-10 years of age. There was no involvement of the lungs or other organs. An initial course of standard antituberculous treatment had no effect on the symptoms. Hydroxychloroquine and cyclosporine A were also ineffective, and the latter caused impaired renal function. Partial symptomatic relief was obtained with prednisolone and increased benefit was observed in combination with methotrexate. Subsequent introduction of the TNF-alpha inhibitor eternacept did not discernibly benefit the clinical condition, but was associated with recurrent infections. In contrast, a trial of infliximab therapy demonstrated clinical efficacy and eliminated all symptoms, restoring a high quality of life. At follow up at 20 years of age (after 2-5 years of infliximab treatment) the twins had an almost normal physical appearance and a normal psychomotoric development, indicating a favourable short-term prognosis of the disease. Blau syndrome has pathologic, clinical and therapeutic features in common with sarcoidosis, but rarely involves the lungs or other parenchymatous organs. In children, discrimination between early onset sarcoidosis and Blau syndrome should include a CARD15 mutation analysis. 相似文献
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Nobuo Kanazawa 《Nihon Rinshō Men'eki Gakkai kaishi》2007,30(2):123-132
Sarcoidosis is a systemic inflammatory disease clinically characterized by swelling of bilateral hilar lymph nodes and histologically defined by non-caseating epithelioid cell granulomas. Among child cases, a special subtype, called the early-onset sarcoidosis, is known to appear in children younger than 4 years of age and to be characterized by a distinct triad of skin, joint and eye disorders without pulmonary involvement. On the other hand, autosomal dominantly-transmitted disease with a characteristic features similar to those of early-onset sarcoidosis has been reported as Blau syndrome. By a linkage analysis, the responsible gene for Blau syndrome has been mapped close to the IBD (Inflammatory Bowel Disease) 1 locus. After CARD15 (NOD2), originally identified as the susceptibility gene for Crohn's disease, was also proved to be responsible for Blau syndrome, the same gene mutations have been found in sporadic early-onset sarcoidosis cases. Nod2 recognizes a signal from bacterial cell wall component in the cytoplasm of monocytic cells to activate NF-kappaB, and thus can work as an intracellular sensor of bacteria. While the loss-of-function mutations in its LRR domain are associated with Crohn's disease, Blau syndrome and early-onset sarcoidosis are autoinflammatory diseases that are caused by the gain-of-function mutations in its NOD domain. 相似文献
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Blau syndrome (BS) is an autosomal dominantly inherited disease characterized by granulomas and arthritis. The gene mutated in BS was recently found to be CARD15. Mutations in this gene also occur in about 20% of patients with Crohn's disease (CD), though with different mutations than in the Crohn's patients. We are not aware of any cure or specific treatment for BS. We have found that bupropion is effective for CD, and we now suggest that bupropion be considered for treatment of BS. 相似文献
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Familial Blau syndrome and sporadic early-onset sarcoidosis (EOS) are both systemic granulomatous diseases evoked by the spontaneous activation of mutated NOD2. In Japan, the R334W amino acid substitution is more frequently identified, whereas the R334Q mutation is rare and, in contrast to western countries where disease causing mutations are typically hereditary, most Japanese cases derive from sporadic mutations. Recently, a case with a six-base deletion in the NOD2 gene was reported. This Blau syndrome/EOS patient presented with the unpainful soft swelling of the dorsal side of the wrist and ankles, as well as flexion contracture at the proximal interphalangeal joint that gradually appeared during their clinical course. These features are useful for the differential diagnosis of Blau syndrome/EOS from juvenile idiopathic arthritis. Owing to their characteristic clinical symptoms, Blau and EOS patients can be identified earlier if medical experts become more acquainted with these distinctions. Even though specific treatment based on pathophysiologic mechanism has not been explored yet, early diagnosis will prevent the progression to severe impairment, which can severely affect patients' lives. 相似文献
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Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn's disease 总被引:13,自引:0,他引:13
Chronic inflammatory bowel diseases (IBDs), specifically Crohn's disease (CD) and ulcerative colitis (UC), have increased
significantly in western countries and Japan over the last decade, but very little is known about their pathogenesis. A candidate-gene
approach recently identified NOD2/CARD15 as one susceptibility gene from the IBD1 locus on chromosome 16. Alterations in this gene were found in many Caucasian patients with CD; in particular, two nonsynonymous
substitutions (R702W and G908R) and a frameshift mutation (1007fs) were shown to be independent risk factors for CD. We investigated
DNA from 483 Japanese CD patients to detect those three mutations in NOD2/CARD15 by appropriate genotyping techniques, but found only an R702Q substitution in a single patient. Direct sequencing of DNA
from 96 of our patients in the regions containing the three reported major mutations detected no sequence alterations of consequence.
Our findings indicate that the NOD2/CARD15 gene is not a major contributor to CD susceptibility in the Japanese population.
Received: May 15, 2002 / Accepted: May 21, 2002 相似文献
8.
Bialecka M Kurzawski M Klodowska-Duda G Opala G Juzwiak S Kurzawski G Tan EK Drozdzik M 《Neuroscience research》2007,57(3):473-476
Recent reports have proven the importance of genetic factors and inflammation in the pathogenesis of sporadic Parkinson's disease (PD). In the current study, the frequency of CARD15/NOD2 gene variants (R702W, G908R, L1007fs), previously associated with Crohn's disease--a common inflammatory bowel disease, have been examined in a group of 308 sporadic PD patients and 220 healthy controls. Significantly higher frequency of total CARD15 variant alleles in PD patients (13.0%) compared to the controls (8.0%, p<0.02) was observed. 24.0% of PD patients carried at least one CARD15 variant allele compared to 15.5% of healthy controls (p<0.02, OR=1.73). The results of the study suggest, that the polymorphism in CARD15/NOD2 gene may be a risk factor for sporadic PD development, and support the concept of inflammatory pathogenesis of PD. 相似文献
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Akahoshi M Ishihara M Namba K Kitaichi N Ando Y Takenaka S Ishida T Ohno S Mizuki N Nakashima H Shirakawa T 《Tissue antigens》2008,71(6):564-567
CARD15 was first identified as a susceptibility gene for Crohn's disease. More recently, CARD15 mutations were shown to be associated with the pediatric granulomatous inflammatory diseases, Blau syndrome and early-onset sarcoidosis (EOS). The aim of the present study was to evaluate whether CARD15 variants also play a role in patients with ordinary sarcoidosis other than EOS. We enrolled 135 Japanese sarcoidosis patients with uveitis as well as 95 healthy individuals and performed mutation analysis by direct sequencing of CARD15 exon 4. Direct DNA sequencing in the sarcoidosis patients showed eight CARD15 variants, including five novel mutations (13402C>T, 13543C>T, 13775C>A, 13937G>A, and 14079C>T). Compared with healthy individuals, CARD15 mutations are not common in the Japanese patients with sarcoidosis. Based on the results, we examined the clinical manifestations in patients with sarcoidosis according to their CARD15 mutations. Sarcoidosis patients with these mutations have no specific clinical features with regard to course of the disease or disease severity. Our results indicate that in general, CARD15 mutations may not contribute to the risk of sarcoidosis. 相似文献
10.
Mayor NP Shaw BE Keshav S Madrigal JA Marsh SG 《Journal of immunological methods》2007,327(1-2):82-87
The Nucleotide-binding Oligomerisation Domain (NOD) 2 protein is encoded by the Caspase Recruitment Domain (CARD) 15 gene and has a critical role in innate immunity. Recent studies have implicated Single Nucleotide Polymorphisms (SNPs) of the NOD2/CARD15 gene with the onset of several Inflammatory Bowel Disorders (Crohn's Disease, Blau syndrome) and the progression of several malignant diseases. The identification of SNPs in the genotypes of donor and recipient pairs prior to haematopoietic stem cell transplantation have also been shown to predict for a worse outcome, specifically causing increases in the incidence and severity of acute Graft-versus-Host disease, disease relapse and mortality. In light of these widespread areas of interest, we have developed a Polymerase Chain Reaction assay using Sequence Specific Primers (PCR-SSP) to identify the three SNPs that have been implicated, (SNPs 8, 12 and 13). The assay has proven to be a rapid and accurate method of performing NOD2/CARD15 genotyping when compared to other techniques described to date. 相似文献
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S. Manouvrier-Hanu B. Puech F. Piette O. Boute-Benejean A. Desbonnet B. Duquesnoy J.P. Farriaux 《American journal of medical genetics. Part A》1998,76(3):217-221
Blau syndrome (MK186580) comprises granulomatous arthritis, iritis, and skin rash, and is an autosomal-dominant trait with variable expressivity. So far it was described in 5 families. We report on a sixth family with severe progression of eye involvement and discuss the nosology with similar diseases, such as early-infantile sarcoidosis. Am. J. Med. Genet. 76:217–221, 1998. © 1998 Wiley-Liss, Inc. 相似文献
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A patient with Marfan syndrome was shown to be heterozygous for a G to A transition at nucleotide 3952 of the FBNI gene. This would result in a cysteine to tyrosine substitution at amino acid 1223 in the fibrillin protein. 相似文献
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Jimenez-Martinez MC Cruz F Groman-Lupa S Zenteno JC 《International journal of immunogenetics》2011,38(3):233-242
The genetic and immunophenotypic characteristics of a 3-year-old patient with Blau syndrome (BS), an early onset sarcoidosis caused by mutations in NOD2, were investigated. Molecular analysis of NOD2 gene was achieved by PCR and direct nucleotide sequencing. Immunophenotyping included cytometric analysis of memory-effector markers on T-cells, and cytokine in serum, aqueous humour and vitreous. A novel M513R mutation in NOD2 was demonstrated. Immunophenotyping revealed higher frequency of CCR4+ cells and CCR9+ cells on CD4+ cells; most CD8+ cells were CCR7- and CCR9+. IL6 and IL-8 were detected in a gradient manner: vitreous humour>aqueous humour>serum. The immunophenotype in this patient was characterized by a differential expression of chemokine receptors on T cells and by a particular ocular microenvironment enriched in IL-6 and IL-8. To our knowledge, this is the first study analysing the immunological features of BS at aqueous humour, vitreous and blood levels. Our results expand the knowledge of the genetic and immunopathological basis of BS. 相似文献
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Kutikhin AG 《Human immunology》2011,72(10):955-968
NOD1/CARD4 and NOD2/CARD15 are members of Nod-like receptor family. They are located in cytosol, bind bacterial and viral ligands and play a key role in realization of innate and adaptive immune response, apoptosis, autophagy, and reactive oxygen species generation. Polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may be associated with altered risk of gastric, colorectal, breast, ovarian, prostate, testicular, lung, laryngeal, liver, gallbladder, biliary tract, pancreatic, small bowel, kidney, urinary bladder cancer, skin cancer, nonthyroid endocrine tumors, lymphoma and leukemia. The short list of such polymorphisms perspective for oncogenomic investigations may include rs2006847, rs2066845, rs2066844, rs2066842, ND(1)+32656, rs2075820 whereas rs104895493, rs104895476, rs104895475, rs104895474, rs104895473, rs104895472, rs104895462, rs104895461, rs104895460, rs104895438, rs5743291, rs5743260, rs2076756, rs2066843, Pro371Thr, Ala794Pro, Gln908His, rs72551113, rs72551107, rs6958571, rs2907749, rs2907748, rs2075822, rs2075819, rs2075818 may be added to the extended list. Reasons of discrepancies between different studies include confounding host genetic, bacterial, or environmental factors modulating penetrance of variant allele and affecting risk of condition increasing cancer risk, different bacterial impact in aetiology of such conditions, differences in sample size, clinicopathological characteristics, diagnostics, stratification, genotyping methods, and chance. 相似文献
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Germline mutations of the LKB1 gene are associated with Peutz-Jeghers syndrome (PJS), which is characterized by mucocutaneous pigmentation and gastrointestinal hamartoma with an increased risk of cancer development. In this study, we have employed polymerase chain reaction and DNA sequencing analysis to characterize the LKB1 gene in a 25-year-old Japanese PJS patient. Direct sequence analyses revealed a novel single base deletion at nucleotide 844 in exon 6 (844delC) in one LKB1 allele, resulting in a frame shift and in the introduction of a premature termination codon in this mutated allele. 相似文献
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Liehr T Starke H Heller A Weise A Beensen V Senger G Kittner G Prechtel M Claussen U Seidel J 《International journal of molecular medicine》2003,11(5):575-577
We report on the fourth known case with an interstitial deletion in 15q21. In the present case the breakpoints have been determined by GTG-banding, microdissection and the recently developed multicolor banding (MCB) technique as 15q21.1-q21.3. Common features in all four cases are mental retardation, growth retardation, a beak-like nose with hypoplastic alae nasi and a thin upper lip. Additional frequent features are small hands and feet, hypotonia, low hair implantation, low set ears, clinodactyly and obesity. The possibility that a critical region for a new microdeletion-syndrome is situated in 15q21 is discussed. 相似文献
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Prasad C Marles S Prasad AN Nikkel S Longstaffe S Peabody D Eng B Wright S Waye JS Nowaczyk MJ 《American journal of medical genetics》2002,108(1):64-68
Smith-Lemli-Opitz syndrome (SLOS) (Online Mendelian Inheritance in Man, OMIM, 2001, http://www.ncbi.nlm.nih.gov/omim/ for SLOS, MIM 270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 3beta-hydroxysterol Delta(7)-reductase gene, DHCR7. We report on a female infant with an exceptionally mild phenotype of SLOS, in whom molecular studies identified a new mutation in DHCR7. The proposita initially presented with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of her toes in both feet. The plasma cholesterol was borderline low at 2.88 mmol/L (normal 2.97-4.40 mmol/L). Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Molecular analysis demonstrated compound heterozygosity for IVS8-1G -->C and Y280C, a new missense mutation in DHCR7. Since the other mutation in this patient is a known null mutation, this newly discovered mutation is presumably associated with significant residual enzyme activity and milder expression of clinical phenotype. 相似文献
20.
van der Paardt M Crusius JB de Koning MH Murillo LS van de Stadt RJ Dijkmans BA Peña AS van der Horst-Bruinsma IE 《Genes and immunity》2003,4(1):77-78
An insertion mutation at nucleotide 3020 (3020insC) and a missense mutation G2722C in the CARD15 gene on chromosome 16p have been reported to be associated with Crohn's disease (CD). The protein encoded by the CARD15 gene is expressed in peripheral monocytes and regulates apoptosis and NF-kappaB activation, factors which play an important role in inflammation. Since CD and ankylosing spondylitis (AS) are interrelated disorders, we have investigated whether these mutations in the CARD15 gene are also associated with AS. We studied 113 unrelated AS patients and 152 unrelated healthy controls. No significant differences were found between patients and controls in the prevalence of the insertion 3020insC mutation and the G2722C missense mutation, OR = 1.36, 95% CI: 0.27-6.84, P = 0.70 and OR = 0.58; 95% CI: 0.18-1.94; P = 0.38, respectively. We conclude that the insertion 3020insC mutation and the G2722C missense mutation in the CARD15 gene are not involved in the susceptibility to AS. 相似文献