Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.

• Klíčová slova
• Cytometry, Exhaustion, IL-7, Immunodeficiency, Lymphopenia, Peritoneal dialysis, RNA-seq, SIOD, Schimke Imunoosseous dysplasia, Schimke immuno-osseous dysplasia, Spectral Cytometry, T cell, Thymus,
• MeSH
• apoptóza genetika   MeSH
• arterioskleróza genetika   etiologie   imunologie   MeSH
• dítě MeSH
• DNA-helikasy genetika   MeSH
• lidé MeSH
• metabolické nemoci kostí etiologie   genetika   MeSH
• nefrotický syndrom etiologie   genetika   MeSH
• oprava DNA * genetika   MeSH
• osteochondrodysplazie * genetika   imunologie   MeSH
• plicní embolie genetika   etiologie   MeSH
• poruchy růstu genetika   etiologie   MeSH
• primární imunodeficience * genetika   diagnóza   imunologie   MeSH
• syndromy imunologické nedostatečnosti genetika   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA-helikasy MeSH
• SMARCAL1 protein, human MeSH Prohlížeč

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

• MeSH
• arterioskleróza diagnóza   genetika   patologie   MeSH
• dítě MeSH
• DNA-helikasy genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetické testování MeSH
• genotyp MeSH
• kohortové studie MeSH
• kojenec MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• nefrotický syndrom diagnóza   genetika   patologie   MeSH
• osteochondrodysplazie diagnóza   genetika   patologie   MeSH
• plicní embolie diagnóza   genetika   patologie   MeSH
• předškolní dítě MeSH
• primární imunodeficience MeSH
• syndromy imunologické nedostatečnosti diagnóza   genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-helikasy MeSH
• SMARCAL1 protein, human MeSH Prohlížeč

High plasma triglyceride levels have been suggested to be independent risk factors of cardiovascular disease development and cardiovascular diseases are the most common cause of death in industrial countries around the world. It is known, that plasma levels of triglycerides are partially genetically determined. The importance of apoAV gene for determination of plasma triglyceride levels has been suggested by creations of transgenic and knock-out mice and confirmed on population studies. More then ten variants have been described in the human apoAV gene. Associations between four of them (T-1131-->C, Serl19-->Trp, Val153-->Met a Cys185-->Gly) and plasma triglyceride levels have been intensively analysed in different populations. Although with some differences between ethnic groups, alleles C-1131, Trp19 a Cys185 (so far detected just in Chinese population) are connected with elevated levels of plasma triglycerides. First analysis have detected that T-11131-->C a Ser19-->Trp apoAV variants could influence risk of myocardial infarction and size of LDL particles. Val153-->Met polymorphism is not associated with plasma levels of triglycerides, but females homozygous for Val153 have elevated levels of plasma HDL cholesterol.

• MeSH
• apolipoprotein A-V MeSH
• apolipoproteiny A MeSH
• apolipoproteiny genetika   fyziologie   MeSH
• arterioskleróza krev   genetika   MeSH
• frekvence genu MeSH
• genetická variace MeSH
• hypertriglyceridemie krev   genetika   MeSH
• infarkt myokardu genetika   MeSH
• koronární nemoc genetika   MeSH
• lidé MeSH
• rizikové faktory MeSH
• triglyceridy krev   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• APOA5 protein, human MeSH Prohlížeč
• apolipoprotein A-V MeSH
• apolipoproteiny A MeSH
• apolipoproteiny MeSH
• triglyceridy MeSH

Apolipoprotein (apo) B-100 is a key protein compound of plasma lipid metabolism. This protein, as a sole component of LDL particles, to a great extent controls the homeostasis of LDL cholesterol in the plasma. Therefore, this protein and its structural variants play an important role in development of hyperlipidemia and atherosclerosis. Intensive research into the structure and biological functions of apoB-100 has led to identification of its complete structure as well as the responsible binding sites. With the development of the methods of molecular biology, some structural variants of the apoB-100 protein that directly affect its binding properties have been described. These are mutations leading to amino acid substitution at positions 3500 (R3500Q and R3500W) and 3531 (R3531C) that have been shown to decrease the binding affinity of apoB-100 in vitro. However, only the former mutations have been unequivocally demonstrated to cause hyperlipidemia in vivo. This minireview is aimed to discuss the impact of apoB-100 and its structural variants on plasma lipid metabolism and development of hyperlipidemia.

• MeSH
• apolipoprotein B-100 MeSH
• apolipoproteiny B genetika   metabolismus   MeSH
• arterioskleróza genetika   metabolismus   MeSH
• hyperlipidemie genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• apolipoprotein B-100 MeSH
• apolipoproteiny B MeSH

It has been hypothesized that mutational events may be involved in the atherogenetic process and that at least a portion of atherosclerotic plaques may be the results of monoclonal proliferation of a single mutated smooth muscle cell (SMC). Therefore, atherosclerosis may be similar to carcinogenesis and may have an environmental etiology. We have analyzed bulky-aromatic DNA adducts in human thoracic aortas from male subjects, aged between 30-60 years, who died suddenly or accidentally, and who had been examined by autopsy within 24 h after death. We found significantly (P < 0.001) higher DNA adduct levels in the samples from subjects with frequent atherosclerotic changes in the whole body ("Cases", N = 76) compared with those having few atherosclerotic changes ("Controls", N = 57). We also observed a significantly elevated weight of heart and plasma levels of total and LDL cholesterol in "Cases" vs "Controls". Significant differences in DNA adduct levels between smokers and nonsmokers were observed in "Controls" only. Multivariate linear regression analyses with age-adjusted data confirmed a significant influence of LDL cholesterol (P < 0.001), vitamin A (P < 0.01), smoking behavior (P < 0.05; evaluated as plasma cotinine levels) and NAT2 genotypes (P < 0.05) on bulky-aromatic DNA adduct levels. The induction of DNA adducts suggests that alterations at the DNA level may contribute to the development of atherosclerosis. Furthermore, atherogenesis and carcinogenesis may share a similar etiology, i.e. genotoxic action of environmental chemicals.

• MeSH
• adukty DNA * MeSH
• aorta thoracica patologie   MeSH
• arterioskleróza genetika   patofyziologie   MeSH
• dospělí MeSH
• kouření škodlivé účinky   MeSH
• LDL-cholesterol krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• pitva MeSH
• regresní analýza MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adukty DNA * MeSH
• LDL-cholesterol MeSH

In this study we compared several parameters characterizing differences in the lipoprotein profile between members of families with a positive or negative family history of coronary artery disease (CAD). In addition to regular parameters such as the body mass index (BMI), total plasma cholesterol (TC), low density (LDL-C) and high density (HDL-C) cholesterol and triglycerides (TG) we estimated the fractional esterification rate of cholesterol in apoB lipoprotein-depleted plasma (FER(HDL)) which reflects HDL and LDL particle size distribution. A prevalence of smaller particles for the atherogenic profile of plasma lipoproteins is typical. Log (TG/HDL-C) as a newly established atherogenic index of plasma (AIP) was calculated and correlated with other parameters. The cohort in the study consisted of 29 young (< 54 years old) male survivors of myocardial infarction (MI), their spouses and at least one offspring (MI group; n=116). The control group consisted of 29 apparently healthy men with no family history of premature CAD in three generations, their spouses and at least one offspring (control group; n=124). MI families had significantly higher BMI than the controls, with the exception of spouses. Plasma TC did not significantly differ between MI and the controls. MI spouses had significantly higher TG. Higher LDL-C had MI survivors only, while lower HDL-C had both MI survivors and their spouses compared to the controls. FER(HDL) was significantly higher in all the MI subgroups (probands 25.85+/-1.22, spouses 21.55+/-2.05, their daughters 16.93+/-1.18 and sons 19.05+/-1.33 %/h) compared to their respective controls (men 20.80+/-1.52, spouses 14.70+/-0.98, daughters 13.23+/-0.74, sons 15.7+/-0.76 %/h, p<0.01 to p<0.05). Log(TG/HDL-C) ranged from negative values in control subjects to positive values in MI probands. High correlation between FER(HDL) and Log (TG/HDL-C) (r=0.80, p<0.0001) confirmed close interactions among TG, HDL-C and cholesterol esterification rate. The finding of significantly higher values of FER(HDL) and Log (TG/HDL-C) indicate higher incidence of atherogenic lipoprotein phenotype in members of MI families. The possibility that, in addition to genetic factors, a shared environment likely contributes to the familial aggregation of CAD risk factors is supported by a significant correlation of the FER(HDL) values within spousal pairs (control pairs: r=0.51 p<0.01, MI pairs: r=0.41 p<0.05).

• MeSH
• apolipoproteiny B krev   MeSH
• arterioskleróza krev   etiologie   genetika   MeSH
• cholesterol krev   MeSH
• dospělí MeSH
• estery cholesterolu krev   MeSH
• HDL-cholesterol krev   MeSH
• index tělesné hmotnosti MeSH
• infarkt myokardu krev   genetika   MeSH
• kohortové studie MeSH
• koronární nemoc krev   etiologie   genetika   MeSH
• LDL-cholesterol krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipoproteiny HDL krev   MeSH
• lipoproteiny LDL krev   MeSH
• lipoproteiny krev   MeSH
• mladiství MeSH
• triglyceridy krev   MeSH
• velikost částic MeSH
• životní prostředí MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• apolipoproteiny B MeSH
• cholesterol MeSH
• estery cholesterolu MeSH
• HDL-cholesterol MeSH
• LDL-cholesterol MeSH
• lipoproteiny HDL MeSH
• lipoproteiny LDL MeSH
• lipoproteiny MeSH
• triglyceridy MeSH

Apolipoprotein E (apoE) is a plasma lipoprotein which plays a basic role in the degradation of particles rich in cholesterol and triglycerides. It is able to bind to LDL receptors, but also to receptors for chylomicron remnants. There are three major apoE isoforms, E2, E3, and E4. Their role in lipoprotein metabolism is related to their affinity for receptors. Allele E3 is predominant and apoE3 affects metabolism of lipoproteins in a standard way. When compared to allele E3, allele E2 is associated with lower LDL levels, whereas allele E4 with higher LDL levels. This has an impact on the progression of atherosclerosis. Allele E2 exhibits a protective role, whereas allele E4 is associated with a high risk factor. Lipoprotein(a) [Lp(a)] is a plasma lipoprotein, consisting of apolipoprotein(a), linked by a covalent bond with the LDL particle. Increased Lp(a) levels are associated with an increased incidence of diseases based on atherosclerosis, namely the ischemic heart disease. Another effect of Lp(a) is its competition with plasminogen, resulting in a decrease of fibrinolysis and thrombogenic activity. ApoE and Lp(a) are independent risk factors for premature development of atherosclerosis and therefore can be considered as candidate genes of premature atherosclerosis.

• MeSH
• alely MeSH
• Alzheimerova nemoc krev   genetika   metabolismus   MeSH
• apolipoproteiny E krev   chemie   genetika   metabolismus   MeSH
• apolipoproteiny krev   chemie   genetika   metabolismus   MeSH
• arterioskleróza krev   epidemiologie   genetika   metabolismus   MeSH
• genetická predispozice k nemoci MeSH
• hyperlipoproteinemie krev   genetika   metabolismus   MeSH
• lidé MeSH
• lipoprotein (a) krev   chemie   genetika   metabolismus   MeSH
• lipoproteiny LDL metabolismus   MeSH
• protein - isoformy krev   chemie   genetika   metabolismus   MeSH
• věk při počátku nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• apolipoproteiny E MeSH
• apolipoproteiny MeSH
• lipoprotein (a) MeSH
• lipoproteiny LDL MeSH
• protein - isoformy MeSH

• MeSH
• arterioskleróza enzymologie   genetika   MeSH
• cystathionin-beta-synthasa genetika   MeSH
• dítě MeSH
• dospělí MeSH
• inzerční mutageneze * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• polymorfismus genetický * MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystathionin-beta-synthasa MeSH

Apolipoprotein E (apo E) is a genetically polymorphous glykoprotein made up of 299 amino acids. It is an important part of triacylglycerol rich lipoproteins [chylomicrons, lipoproteins with a very low density (VLDL) and their "residues"]. Apo E is a ligand of apo B, E receptors and thus regulates in a marked way the homeostasis of lipids and lipoproteins in plasma. The genetic polymorphism of apo E is controlled by three alleles epsilon 2, epsilon 3, epsilon 4 which influence individual plasma cholesterol levels and thus the process of atherogenesis. Lipoprotein (a) [Lp(a)] is a plasma lipoprotein which is another independent, genetically determined risk factor in the process of atherogenesis. The basis of its structure is a micelle of LDL which is linked by a disulphidic covalent with the glycoprotein of the apolipoprotein (a). Lp (a) was detected in atherosclerotic plaques and it is assumed that it participates in the penetration of lipids into the vascular wall. Its thrombogenic properties were also detected due to its structural relationship with plasminogen to which it is linked and inhibits competitively the transformation of plasminogen to plasmin.

• MeSH
• Alzheimerova nemoc metabolismus   MeSH
• apolipoproteiny E genetika   metabolismus   MeSH
• arterioskleróza genetika   metabolismus   MeSH
• diabetes mellitus 2. typu genetika   metabolismus   MeSH
• lidé MeSH
• lipoprotein (a) genetika   metabolismus   MeSH
• populační genetika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• apolipoproteiny E MeSH
• lipoprotein (a) MeSH

The purpose of this study was to assess the effect of the main risk factors for cardiovascular disease on the process of subclinical atherosclerosis in originally borderline hypertensives. The relation of far wall common carotid artery intima-media thickness (IMT CCA) measured by B-mode ultrasound to smoking, body mass index (BMI), blood pressure, lipids, and angiotensin-converting enzyme (ACE) gene polymorphism was analyzed. In 48 subjects examined (mean age, 61.9 +/- 2.54 years), median IMT CCA was 0.708 mm. Statistically significant differences in BMI (26.5 vs. 29.2 kg/m2, p < 0.025) and HDL-cholesterol level (1.42 vs. 1.1 mmol/l, p < 0.025) between the first and third tertile of IMT CCA were found. No differences were observed between "controls" and "cases" in blood pressure, total cholesterol, and triacylglycerols. No significant differences in IMT CCA were found between smokers and nonsmokers and among different alleles of the ACE gene. These data reflect the importance of HDL-cholesterol and BMI on the process of atherosclerosis within an otherwise homogeneous group of patients.

• MeSH
• arteria carotis communis diagnostické zobrazování   MeSH
• arterioskleróza komplikace   diagnostické zobrazování   genetika   MeSH
• dospělí MeSH
• HDL-cholesterol krev   MeSH
• hypertenze komplikace   diagnostické zobrazování   MeSH
• index tělesné hmotnosti MeSH
• kohortové studie MeSH
• kouření škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci arterie carotis komplikace   diagnostické zobrazování   genetika   MeSH
• neparametrická statistika MeSH
• polymorfismus genetický MeSH
• renin-angiotensin systém genetika   MeSH
• rizikové faktory MeSH
• rozdělení chí kvadrát MeSH
• tunica intima diagnostické zobrazování   MeSH
• ultrasonografie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• HDL-cholesterol MeSH