The aim of this study was to describe the clinical and molecular genetic findings in seven individuals from three unrelated families with Blau syndrome. A complex ophthalmic and general health examination including diagnostic imaging was performed. The NOD2 mutational hot spot located in exon 4 was Sanger sequenced in all three probands. Two individuals also underwent autoinflammatory disorder gene panel screening, and in one subject, exome sequencing was performed. Blau syndrome presenting as uveitis, skin rush or arthritis was diagnosed in four cases from three families. In two individuals from one family, only camptodactyly was noted, while another member had camptodactyly in combination with non-active uveitis and angioid streaks. One proband developed two attacks of meningoencephalitis attributed to presumed neurosarcoidosis, which is a rare finding in Blau syndrome. The probands from families 1 and 2 carried pathogenic variants in NOD2 (NM_022162.3): c.1001G>A p.(Arg334Gln) and c.1000C>T p.(Arg334Trp), respectively. In family 3, two variants of unknown significance in a heterozygous state were found: c.1412G>T p.(Arg471Leu) in NOD2 and c.928C>T p.(Arg310*) in NLRC4 (NM_001199139.1). In conclusion, Blau syndrome is a phenotypically highly variable, and there is a need to raise awareness about all clinical manifestations, including neurosarcoidosis. Variants of unknown significance pose a significant challenge regarding their contribution to etiopathogenesis of autoinflammatory diseases.
- MeSH
- artritida * genetika diagnóza MeSH
- dědičné zánětlivé autoimunitní nemoci MeSH
- lidé MeSH
- lymfedém genetika diagnóza MeSH
- mutace * MeSH
- nemoci centrálního nervového systému MeSH
- neuropatická artropatie genetika diagnóza MeSH
- rodokmen * MeSH
- sarkoidóza * genetika diagnóza MeSH
- sekvenování exomu MeSH
- signální adaptorový protein Nod2 * genetika MeSH
- synovitida * genetika diagnóza MeSH
- uveitida * genetika diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Blau syndrome (BS) is an auto-inflammatory granulomatous disease that possibly involves abnormal response to interferon gamma (IFNγ) due to exaggerated nucleotide-binding oligomerization domain containing 2 (NOD2) activity. Mendelian susceptibility to mycobacterial diseases (MSMD) is an infectious granulomatous disease that is caused by impaired production of or response to IFNγ. We report a mother and daughter who are both heterozygous for NOD2c.2264C˃T variant and dominant-negative IFNGR1818del4 mutation. The 17-year-old patient displayed an altered form of BS and milder form of MSMD, whereas the 44-year-old mother was completely asymptomatic. This experiment of nature supports the notion that IFNγ is an important driver of at least some BS manifestations and that elucidation of its involvement in the disease immunopathogenesis may identify novel therapeutic targets.
- MeSH
- artritida genetika MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mutace genetika MeSH
- receptory interferonů nedostatek genetika MeSH
- sarkoidóza genetika MeSH
- signální adaptorový protein Nod2 genetika MeSH
- synovitida genetika MeSH
- uveitida genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
PURPOSE: Crohn's disease (CD) belongs to chronic disorders with unpredictable disease course. The aim of this study was to identify how genetic testing (NOD2/CARD15) can be used in patients with CD to predict the need for surgical treatment (to define an aggressive type of disease where the patient can profit from early surgery). METHODS: The patients who were tested genetically had undergone a surgery due to CD at the Department of Surgery University Hospital Brno Bohunice between 2010 and 2016. The control group consisted of patients with CD who had been diagnosed with CD at least 5 years prior to the testing and had not required any surgical intervention. The second control group was healthy subjects. RESULTS: In total, there were 117 operated patients for CD, 77 patients with CD that had not undergone surgery for CD and 30 healthy subjects. For patients with at least one genetic mutation, the risk of the necessity of surgical treatment of CD is 1.96 times higher than for patients with no mutation. Patients with two or more mutations were generally operated on at a younger age, in a shorter time after being diagnosed and each patient had a partial resection of the ileum. CONCLUSION: The group of operated patients with CD had a significantly higher distribution of at least one genetic mutation as opposed to the non-operated group. In patients with two or more mutations, the disease course was more aggressive. This group of patients might profit from the conservative top-down or early surgical therapy.
- MeSH
- alely MeSH
- Crohnova nemoc genetika chirurgie MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- prognóza MeSH
- rizikové faktory MeSH
- signální adaptorový protein Nod2 genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND OBJECTIVES: Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). The aim of this study was to determine the relationship between the presence of these variants and disease phenotype. MATERIAL AND METHODS: 70 patients with Crohn's disease were examined for the presence of the above-mentioned mutations. The researchers used the medical records to retrospectively obtain clinical data and together with the information obtained prospectively according to the protocol they analysed the connection between gene mutations and disease phenotype. RESULTS: At least one mutation was found in 22 patients with Crohn's disease (32%), four patients were found to have two different mutations (composed heterozygotes - 6%) and six patients (9%) were homozygotes for the 3020insC gene. No significant differences were found between the groups with wild-type form and the mutated form of the NOD2 / CARD15 gene with respect to age at the time of diagnosis, form of the disease or localization according to the Montreal classification. CONCLUSION: Mutations of the NOD2 / CARD15 gene did not significantly affect the frequency of reoperations, homozygotes with 3020insC gene mutations, however, represented a high risk group. The phenotype was not related significantly to the presence of the examined mutations.
- MeSH
- Crohnova nemoc genetika chirurgie MeSH
- dospělí MeSH
- fenotyp MeSH
- genetická predispozice k nemoci genetika MeSH
- heterozygot MeSH
- homozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- prospektivní studie MeSH
- reoperace MeSH
- senioři MeSH
- signální adaptorový protein Nod2 genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- Crohnova nemoc genetika MeSH
- exprese genu MeSH
- genetická predispozice k nemoci MeSH
- idiopatické střevní záněty * genetika MeSH
- lidé MeSH
- signální adaptorový protein Nod2 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Reduced microbial diversity has been associated with inflammatory bowel disease (IBD) and probiotic bacteria have been proposed for its prevention and/or treatment. Nevertheless, comparative studies of strains of the same subspecies for specific health benefits are scarce. Here we compared two Bifidobacterium longum ssp. longum strains for their capacity to prevent experimental colitis. METHODS: Immunomodulatory properties of nine probiotic bifidobacteria were assessed by stimulation of murine splenocytes. The immune responses to B. longum ssp. longum CCM 7952 (Bl 7952) and CCDM 372 (Bl 372) were further characterized by stimulation of bone marrow-derived dendritic cell, HEK293/TLR2 or HEK293/NOD2 cells. A mouse model of dextran sulphate sodium (DSS)-induced colitis was used to compare their beneficial effects in vivo. RESULTS: The nine bifidobacteria exhibited strain-specific abilities to induce cytokine production. Bl 372 induced higher levels of both pro- and anti-inflammatory cytokines in spleen and dendritic cell cultures compared to Bl 7952. Both strains engaged TLR2 and contain ligands for NOD2. In a mouse model of DSS-induced colitis, Bl 7952, but not Bl 372, reduced clinical symptoms and preserved expression of tight junction proteins. Importantly, Bl 7952 improved intestinal barrier function as demonstrated by reduced FITC-dextran levels in serum. CONCLUSIONS: We have shown that Bl 7952, but not Bl 372, protected mice from the development of experimental colitis. Our data suggest that although some immunomodulatory properties might be widespread among the genus Bifidobacterium, others may be rare and characteristic only for a specific strain. Therefore, careful selection might be crucial in providing beneficial outcome in clinical trials with probiotics in IBD.
- MeSH
- Bifidobacterium klasifikace fyziologie MeSH
- dendritické buňky mikrobiologie patologie MeSH
- HEK293 buňky MeSH
- imunoenzymatické techniky MeSH
- kolitida chemicky indukované prevence a kontrola MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- probiotika farmakologie MeSH
- signální adaptorový protein Nod2 genetika metabolismus MeSH
- síran dextranu toxicita MeSH
- střeva mikrobiologie patofyziologie MeSH
- toll-like receptor 2 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Úvod: Tři jednonukleotidové polymorfismy (SNP) v NOD2/CARD15 genu (3020insC, R702W, G908R) jsou pro Crohnovu chorobu významným rizikovým faktorem. Jejich diagnostické a terapeutické využití v klinické praxi je však doposud limitované. Cílem studie byla analýza možné asociace těchto polymorfismů s rizikem reoperací a posouzenísouvislosti s fenotypem onemocnění. Metody: U 76 pacientů s Crohnovou chorobou a minimální délkou trvání nemoci 5 let byly testovány tři sekvenční varianty NOD2/CARD15 genu (R702W, G908R, 3020insC). Anamnestická a klinická data, včetně chirurgické léčby byly retrospektivně získány ze zdravotnické dokumentace a prospektivně doplňovány podle protokolu studie. Analyzovány byly souvislosti mezi vybranými genovými polymorfismy, nutností reoperací a fenotypem nemoci. Výsledky: U 24 pacientů (32 %) se našla alespoň jedna sledovaná varianta v NOD2/CARD15 genu. 25 pacientů (33 %) bylo reoperováno, 51 (67 %) představovalo kontrolní skupinu. Trend vyšší četnosti reoperací ve skupině s genovou mutací nedosáhl statistické významnosti (p=0,2688). Dva ze čtyř homozygotů (50 %) nesoucích variantu 3020insC byli opakovaně operováni. Neprokázali jsme signifikantní rozdíly mezi soubory s wild formou a mutovanou formou NOD2/8CARD15 genu s ohledem na věk v době diagnózy (p=0,4356), formu onemocnění (p=0,6610) a lokalizaci (p=0,4747) podle Montrealské klasifikace. Závěr: Polymorfismy v NOD2/CARD genu signifikantně neovlivnily četnost reoperací, homozygoti nesoucí mutaci 3020insC genu však představovali vysoce rizikovou skupinu. Fenotyp onemocnění signifikantně nesouvisel s přítomností vyšetřovaných sekvenčních variant.
Introduction: Three NOD2/CARD15 gene variants (3020insC, R702W, G908R) have been identified as genetic risk factors for Crohn's disease patients. However the diagnostic and therapeutic relevance for clinical practice remains limited. The aim of this study was to evaluate the association between these variants, the risk of reoperation and disease phenotype. Methods: In 76 Crohn's disease patients (41 female, 35 male) with a minimum 5 year follow-up, three polymorphisms of the NOD2/CARD15 gene (R702W, G908R, 3020insC) were tested. Detailed clinical and medical history including surgical procedures and reoperations were obtained by reviewing the medical charts and completed prospectively. Association between the need for reoperation, disease phenotypes and gene variants were analyzed. Results: 24 patients (32%) showed at least one NOD2/CARD15 mutation. 25 patients (33%) required reoperation, 51 (67%) represented the control group. The expected trend that patients with NOD2/CARD15 variants have a higher frequency of reoperations was not confirmed to a level of statistical significance (p=0.2688). Two of the four patients (50%) with the 3020insC variant required further surgery. We did not confirm any association between NOD2/CARD15 mutations and age at diagnosis (p=0.4356), behavior (p=0.6610), or localization (p=0.4747) according to the Montreal classification. Conclusion: NOD2/CARD15 polymorphisms did not significantly affect the reoperation rate. Homozygosity for the 3020insC variant in the NOD2/CARD15 gene is associated with a high risk of reoperation. NOD2/CARD15 gene variants are not significantly associated with specific disease phenotypes.
- MeSH
- Crohnova nemoc * genetika chirurgie MeSH
- dospělí MeSH
- fenotyp MeSH
- hodnocení rizik statistika a číselné údaje MeSH
- homozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- polymorfismus genetický MeSH
- prospektivní studie MeSH
- recidiva MeSH
- reoperace * statistika a číselné údaje MeSH
- retrospektivní studie MeSH
- senioři MeSH
- signální adaptorový protein Nod2 * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
Crohnova nemoc se často projevuje čistě jako zánětlivé onemocnění, ale u mnoha pacientů se vyvine v komplikované onemocnění charakterizované tvorbou striktur nebo píštělí. Přesná etiopatogeneze tohoto závažného onemocnění není zcela jednoznačně objasněna, a to i přes veškeré úsilí výzkumu a přes poznání řady dílčích patogenetických mechanizmů. Mnoho studií naznačuje, že se zvýšeným rizikem rozvoje komplikované formy onemocnění souvisí zejména varianty v NOD2/CARD15 genu. Samotná přítomnost variant v NOD2 genu je pouze jen jedním z faktorů přispívajících k rozvoji tohoto onemocnění. U geneticky predisponovaných jedinců v kombinaci s působením faktorů prostředí dochází k porušení vrozené (např. porušená střevní bariéra, dysfunkce Panethových buněk) i adaptivní (např. nerovnováha efektorových a regulačních T lymfocytů a cytokinů, migrace a retence leukocytů) imunitní odpovědi vůči snížené pestrosti střevních komenzálů. Data dosud provedených metaanalýz neposkytují jednoznačné důkazy k podpoře top-down strategie terapie závislé pouze na jediné variantě v NOD2 genu, ale na druhé straně v případě vysoce rizikových pacientů se dvěma variantami v NOD2 genu data ukazují, že cílená a časná intenzivní terapie by mohla být prospěšná. Na tyto otázky by mohly odpovědět další prospektivní studie.
Crohn's disease is often purely inflammatory, but most patients develop complicated disease with strictures or fistulae. Specific etiopathogenesis of this severe disease is not definitely clear despite research efforts and learning of many pathogenetic mechanisms. Many studies have suggested that NOD2 mutations are associated with increased risk of complicated disease. Presence of NOD2 mutation itself is just one of factors contributing to development of this disease. Genetically predisposed individuals in combination with influence of environmental factors result in a disturbed innate (i.e., disturbed intestinal barrier, Paneth cell dysfunction) and adaptive (i.e., imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. Data of meta-analysis made so far provide ambiguous evidence to support top-down therapy based solely on single NOD2 mutations, but suggest that targeted early-intensive therapy for high-risk patients with two NOD2 mutations might be beneficial, but more prospective trials could answer these questions.
Crohn's disease is a chronic immune-mediated intestinal inflammation targeted against a yet incompletely defined subset of commensal gut microbiota and occurs on the background of a genetic predisposition under the influence of environmental factors. Genome-wide association studies have identified about 70 genetic risk loci associated with Crohn's disease. The greatest risk for Crohn's disease represent polymorphisms affecting the CARD15 gene encoding nucleotide-binding oligomerization domain 2 (NOD2) which is an intracellular sensor for muramyl dipeptide, a peptidoglycan constituent of bacterial cell wall. The accumulated evidence suggests that gut microbiota represent an essential, perhaps a central factor in the induction and maintaining of Crohn's disease where dysregulation of normal co-evolved homeostatic relationships between intestinal microbiota and host mucosal immune system leads to intestinal inflammation. Taken together, these findings identify Crohn's disease as a syndrome of overlapping phenotypes that involves variable influences of genetic and environmental factors. A deeper understanding of different genetic abnormalities underlying Crohn's disease together with the identification of beneficial and harmful components of gut microbiota and their interactions are essential conditions for the categorization of Crohn's disease patients, which enable us to design more effective, preferably causative, individually tailored therapy.
- MeSH
- celogenomová asociační studie MeSH
- Crohnova nemoc genetika MeSH
- gastrointestinální trakt mikrobiologie MeSH
- genetická predispozice k nemoci MeSH
- interakce genů a prostředí MeSH
- lidé MeSH
- mikrobiota * MeSH
- polymorfismus genetický MeSH
- signální adaptorový protein Nod2 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
V posledných rokoch sa záujem gastroenterológov sústredil na hľadanie vplyvu genetických faktorov na etiológiu nešpecifických črevných zápalov a kolorektálneho karcinómu. Gén NOD2/CARD15 je stále najprebádanejším z doteraz známych génov a jeho mutáciami sa dá vysvetliť asi 20 % genetickej predispozície na Crohnovu chorobu. Z neskôr identifikovaných génov má v etiológii Crohnovej choroby perspektívne postavenie aj gén IL23R, ATG16L1 a ďalšie. V prípade dedičného kolorektálneho karcinómu dokážeme pomocou genetickej diagnostiky vyselektovať rizikové skupiny pacientov vyžadujúcich intenzívnejšie sledovanie a tým zachytiť včasné, liečiteľné štádia nádorového rastu. Z praktického hľadiska nemá genetická diagnostika črevných zápalov a nádorov zatiaľ screeningový význam a má len nízky prognostický význam. Je potešiteľné, že slovenské genetické pracoviská sa touto diagnostikou zaoberajú a v súlade s modernými trendmi sa naďalej snažia rozširovať jej diapazón.
In recent years, gastroenterologists focused their interest on finding the genetic background of inflammatory bowel disease and colon cancer. NOD2/CARD15 gene is still the most investigated gene of all known genes and its mutations can explain approximately 20% of genetic predisposition to Crohn's disease. From later identified genes that play an important role in the etiology of Crohn's disease, the IL23R and ATG16L1 genes have a perspective place. In the case of hereditary colorectal cancer, we can select by the help of genetic diagnostics, the group of patients with high risk of colon cancer, which requires more intensive monitoring. The aim is to find out the colon cancer in the early, treatable stage. In practical terms, genetic diagnostics of inflammatory bowel disease and colon cancer has no screening and only poor prognostic importance. It is pleasant, that the Slovak genetic workplaces are interested in this issue and in accordance with modern trends they try to expand its diapason.
- MeSH
- chromozomální nestabilita MeSH
- genetické testování * MeSH
- idiopatické střevní záněty * genetika MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- mikrosatelitní nestabilita MeSH
- receptory interleukinů genetika MeSH
- signální adaptorový protein Nod2 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
