Biomedical subjects

Csaba Szalai

Publications and source records attributed to Csaba Szalai.

At least 19 recordsLinked to original sources

PubMed2006

Involvement of TNFalpha -308A promoter polymorphism in the development of asthma in children infected with Chlamydophila pneumoniae.

Several data indicate a connection between Chlamydophila pneumoniae infection and asthma. Although C. pneumoniae is a common cause of infection, not all infected patients develop asthma. This suggests that certain individuals may be genetically predisposed to the chronic effects of C. pneumoniae infection on airway functions. We investigated the possible modifying effect of different polymorphisms on C. pneumoniae infection and on the susceptibility to asthma in 318 children, among those 144 had asthma and 174 had no asthmatic symptoms. C. pneumoniae-specific antibodies were measured by ELISA. Tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and RANTES (regulated on activation normal T cell expressed and secreted) genotypes were determined by PCR-restriction fragment length polymorphism (RFLP). There were no significant differences in the percentage of children positive for C. pneumoniae-specific antibodies between cases and controls. None of the genotypes was associated with altered susceptibility to C. pneumoniae infection. Among asthmatic children carrying the TNFalpha -308A allele, there were significantly more patients positive for C. pneumoniae-specific IgG, than among control children carrying the same allele (20.1% versus 9.2% of asthmatic versus control children, respectively; p = 0.002; odds ratio = 3.52 (1.52-7.53); p = 0.005). This study indicates the possible roles of polymorphisms in the immune system in the susceptibility to asthma in children infected with C. pneumoniae.

Adolescent↗

PubMed2006

The HLA 8.1 ancestral haplotype is strongly linked to the C allele of -429T>C promoter polymorphism of receptor of the advanced glycation endproduct (RAGE) gene. Haplotype-independent association of the -429C allele with high hemoglobinA1C levels in diabetic patients.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

Adolescent↗

PubMed2006

[Pharmacogenomics of asthma: present and perspective].

One main area of pharmacogenomics is the discovery of new drugs and drug targets with molecular genetic or genomic methods; the other is the study of how genomic differences influence the variability in patients responses to drugs. In this review the authors summarise the most important results of this latter issue. Despite the availability of three major classes of therapeutic agents for asthma, it has been estimated that as many as half of asthmatic patients do not respond to treatment with beta2-agonists, leukotriene modifiers or inhaled corticosteroids. Moreover, in some individuals asthma therapy has been associated with serious adverse drug reactions. An estimated 60 to 80% of variability in individual responses to therapy may have genetic bases. All of the currently available data on asthma pharmacogenomics originated from genetic variations in genes of the drug treatment target or target pathways. Results of genetic association studies that investigate responses to beta2-agonist, leukotriene modifier and corticosteroid therapy will be summarised and recent findings in the literature highlighted. Although, at present pharmacogenomics can explain only a fraction of the adverse drug responses, hopefully these results mark the clinical use of genotyping at an individual level as adjunct to pharmacotherapy for asthma and many other diseases.

Administration, Inhalation↗

PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗

PubMed2004

Polymorphism in the promoter region of the apolipoprotein A5 gene is associated with an increased susceptibility for coronary artery disease.

Although triglycerides (TG) are a major risk factor for coronary artery disease (CAD), their exact role is still controversial. Recently, a T/C polymorphism in the promoter region of the apoA5 gene at position 1131 has been found that is associated with an increased plasma TG concentration. We investigated the role of this polymorphism in 308 Hungarian patients with CAD referred to coronary bypass surgery, and in 310 controls recruited from the same area. The prevalence of the apoA5-1131C allele was significantly higher among CAD patients than among controls (10.9% versus 5.7%; P < 0.001, Odds ratio (OR) = 1.99 (1.30-3.04)). Controls carrying the rare C allele had in average 23.0% (P < 0.001), subjects with CAD 13.8% (P < 0.001) higher TG levels compared to common allele homozygotes. The polymorphism was not associated with other conventional CAD risk factors or laboratory data of the patients. In logistic regression models adjusted for age, gender, presence of diabetes, BMI, smoking, LDL-C, HDL-C and hypertension a significantly increased risk of developing CAD was found in patients carrying the apoA5-1131C allele (P < 0.001; OR = 1.98 (1.14-3.48)), suggesting that this allele variant is an independent genetic risk factor for CAD.

Adult↗

PubMed2004

Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary.

The most common form of non-syndromic autosomal recessive deafness (NSRD) is caused by mutations in the gene GJB2, encoding the protein connexin 26 (Cx26). The mutation c.35delG is found in 30-70% of Caucasian NSRD cases, and is abundant (allele frequency of 0.5-2%) in several European populations, while c.167delT is found in the Ashkenazi Jewish population with about 2% frequency. In the current study, using simple PCR-based tests we established an allele frequency of 0.6% in the Hungarian average, and 0.4% in the Romani (Gypsy) populations for the c.35delG mutation, and an allele frequency of 2.4% in the Ashkenazi population for the c.167delT mutation. Our results do not differ significantly from the published data for Caucasian and non-European Ashkenazi populations and they present figures for the Romani population for the first time. Both mutations may be significant causative factors among the NSRD cases of the respective populations in Central Europe.

Adult↗

PubMed2003

Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index.

Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.

Adult↗

PubMed2003

Relationship between the tumor necrosis factor alpha polymorphism and the serum C-reactive protein levels in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, including ulcerative colitis (UC) and Crohn's disease (CD). The aim of the study was to determine the prevalence of the tumor necrosis factor alpha (TNF-alpha) promoter polymorphisms at positions -238 and -308, and to measure the serum CRP levels in CD and UC patients and in a healthy population. The TNF-alpha gene polymorphisms were determined by the PCR-RFLP method. Samples of 74 CD and 50 UC patients and 138 healthy Hungarian volunteers were examined. The G-->A substitution at position -308 (designated the TNF2 allele) was significantly less frequent among IBD patients than in the control group (P=0.0009); 15% of the CD patients and 18% of the UC patients carried the mentioned allele, which was significantly less frequent compared with the healthy population (33%, P=0.0035 and P=0.036, respectively). No difference in the G-->A substitution at position -238 was observed. We found the median CRP levels to be significantly higher in the active phase of the disease than in the inactive phase among the -308A allele carriers (P=0.002), while this difference was not significant when the CRP levels in the active and inactive phases were compared among the -308GG homozygous patients (P=0.084). The decreased frequency of the TNF2 allele (known to be associated with elevated TNF-alpha production) in IBD may determine the severity of IBD through its interaction with plasma CRP levels, and may modify the pathogenesis of this chronic inflammatory disease.

Adult↗

PubMed2003

The development of asthma in children infected with Chlamydia pneumoniae is dependent on the modifying effect of mannose-binding lectin.

BACKGROUND: Although several studies found associations between infection with Chlamydia pneumoniae and asthma, these were mainly restricted to the exacerbation of the symptoms in adults with known asthma. Data about the role of C pneumoniae in the initiation and development of asthma in children are controversial. OBJECTIVE: We investigated the role of C pneumoniae infection in 139 children with asthma, comparing them with 174 healthy control subjects. Furthermore, we studied the modifying effect of mannose-binding lectin (MBL) variant alleles on the susceptibility to asthma in children infected with C pneumoniae. METHODS: C pneumoniae-specific antibodies were measured by means of ELISA, and MBL genotypes were determined by means of PCR-RFLP. RESULTS: There were no significant differences in the percentage of children with positive results for C pneumoniae-specific antibodies between patients and control subjects. Among asthmatic children carrying variant MBL alleles, there were significantly more patients with positive results for C pneumoniae-specific IgG than among control children with variant MBL genotypes (63.7% vs 40.7% of asthmatic vs control children, respectively; odds ratio adjusted for age and sex, 2.21; 95% CI, 1.10-4.41; P =.02). Infected children with variant MBL alleles were found to have a higher risk of asthma development than infected children with normal MBL genotype. This risk was especially high in children with chronic or recurrent infection (positive results for both IgA and IgG; adjusted odds ratio, 5.38; 95% CI, 1.75-14.36; P =.01), but no increased risk was seen in children with current C pneumoniae infection (positive results for IgM). CONCLUSION: This study indicates the important role of variant MBL alleles in the susceptibility to asthma in children infected with C pneumoniae.

Adolescent↗

PubMed2003

Relationship between complement components C4A and C4B diversities and two TNFA promoter polymorphisms in two healthy Caucasian populations.

The RP-C4-CYP21-TNX (RCCX) modules and the tumor necrosis factor (TNF) gene cluster are probably the most polymorphic genomic regions in the human central major histocompatibility complex (MHC). Using definitive methods for genotypic and phenotypic analyses of complement components C4A and C4B, determination of the RCCX length variants, and SSP-PCR/RFLP analyses of TNFA promoter polymorphisms at positions -308 and -238, we studied the complex relationships between the C4 and TNFA polymorphisms in two normal Caucasian populations. The patterns of the RCCX modular structures and the allelic frequency of -308A TNFA (TNF2) were similar between the Budapest (n = 125) and the Ohio (n = 80) Caucasians. However, the frequency of the -238A allele was significantly higher in the Ohio (11.3%) than in the Budapest (1.6%) study population (p < 0.0001). Marked features were found in the RCCX length variants in the TNF2 carriers and noncarriers. Strong associations were found between the C4AQ0 B1 haplotype from the monomodular short (mono-S) RCCX structure and the TNF2 allele, and between the C4A6 B1 haplotype from the bimodular long-short (LS) structure of the RCCX and the TNFA -238A allele. However, 36%-46% of the TNF2 carriers did not associate with a mono-S in both study cohorts, and 57.1% of the TNFA -238A carriers in Ohio did not associate with C4A6, which has a defective complement C5 convertase activity. The carriers of TNF2 allele had significantly lower C4A serum concentration (0.17 +/- 0.08 g/l) than noncarriers (0.23 +/- 0.09 g/l) (p < 0.001). The lowest C4A serum levels were found in TNF2 carriers with mono-S structures (0.14 +/- 0.06 g/l). In essence, our results demonstrated the heterogeneities of the TNFA promoter polymorphisms, and the linkage disequilibrium of TNFA -308A and -238A alleles with complement C4A deficiency and impaired C4A protein function, respectively.

Blotting, Southern↗

PubMed2003

Evolution of the thyrotropin receptor: a G protein coupled receptor with an intrinsic capacity to dimerize.

The rapidly escalating number of genome sequences has emphasized the basic tenants of the schema of life. By the same token comparisons according to specialized function or niche within nature expose genomic strategies to optimize the use of resources and ensure biological success. Increasing complexity may result from diversification, shuffling, and re-arrangement of an otherwise limited functional genomic complement. To further test the concept of relative structural plasticity of the TSH receptor we sequenced the TSHR gene of two Old World monkey species Macaca mulatta and Cercopithecus aethiops, evolutionary removed from Homo sapiens by >20Myr. Both genes encoded a protein of 764 residues. This structure was 99% homologous between the two species of Old World monkeys while C. aethiops was 97% and M. mulatta was 96% homologous to H. sapiens. TSHR sequence comparisons were sought for an additional eight mammals as well as four (two Salmon, Tilapia, and Sea Bass) from teleosts. The amino-acid sequences of the 14 TSH receptors were similar. The most variable sequences were those of the intracellular tail and the distal cysteine-rich C-terminus flanking region of the ectodomain, whereas the trans-membrane domain was most preserved. Some sequences were decidedly H. sapiens specific, while others were primate specific or showed the changes expected of evolutionary descent. Others, however, exhibited "cross-species polymorphism," sometimes at quite remarkable evolutionary distances. As opposed to H. sapiens the sequence differences may have subtle influences on TSHR function or may affect long-range compensation for radical changes in adducts. The two Old World monkeys share with other lower mammals the absence of a glycosylation site at 113-115. Sea Bass and Tilapia have four glycosylation sites, whereas the two salmon receptors have only three. Changes in some critical residues raise questions about variation in function: thus S281 is conserved in all mammals and an important determinant of negative agonist function of TSHR is replaced by R in Sea Bass. Likewise the K183, found at an important transitional region at LRR 6 conserved in all mammals, is represented by M in fish and may contribute to TSHR lutenization in fish. There is no evidence that evolutionary changes in primate receptors are more rapid than that in other mammals and the separation times of different mammals based on silent nucleotide changes of TSHR are closely parallel to archaeological estimates. Results of correlated mutation analysis, referenced to the rhodopsin crystal structure, affirms dimerization of TSHR transmembrane helices. In addition, it suggests the involvement of critical lipid-facing residues in the helices in receptor dimerization and oligomerization. We highlight the value of evolutionary informatics and set the stage for dissecting out potential subtle differences in TSHR function associated with structural variations.

Amino Acid Motifs↗

PubMed2003

Histamine deficiency in gene-targeted mice strongly reduces antigen-induced airway hyper-responsiveness, eosinophilia and allergen-specific IgE.

Histamine is an important mediator released from activated mast cells provoked by allergen and has a substantial role in the pathophysiology of asthma. However, several lines of evidence indicate that histamine could also have important functions in the regulation of basic cell biological processes. We have used histidine decarboxylase gene-targeted (HDC-KO) mice, lacking histamine, to investigate the effect of histamine deficiency in an animal model of asthma. Our previous investigations revealed that HDC-KO mice had fewer mast cells with reduced granular content and defective degranulation characteristics. Ovalbumin (OVA)-sensitized and challenged HDC-KO mice had significantly reduced airway hyper-responsiveness, lung inflammation, bronchoalveolar lavage eosinophilia, and OVA-specific IgE compared with congenic wild-type littermates treated in the same way. Comparing the expression profiles of cytokines, the levels of IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IFN-gamma were significantly lower in the HDC-KO mice in asthmatic late phase, indicating a significantly altered immune response to OVA provocation and challenge. Evaluation of chemokine gene expression revealed that OVA treatment caused elevation of both T(h)1- and T(h)2-type chemokines in wild-type mice, while the chemokine expression was polarized toward a T(h)1 response in HDC-KO mice. According to our results we can suggest that the possible causes of the reduced asthma symptoms in the HDC-KO mice may be the imperfect mast and eosinophil cell system, and an altered immune response to OVA provocation and challenge.

Analysis of Variance↗

PubMed2002

Differences in the genetic background of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus.

OBJECTIVES: According to the recent classification of diabetes mellitus the Latent Autoimmune Diabetes in Adults (LADA) belongs to the group of type 1 autoimmune diabetes, as a slowly progressive form. Our aim was to determine (i) the prevalence of HLA-DRB1 and DQB1 genotypes, and (ii) to determine the tumor necrosis factor (TNF) alpha promoter polymorphism at position -308 (the G-->A substitution, designated the TNF2 allele) in patients with type 1 diabetes and with LADA compared with the healthy population. METHODS: The major histocompatibility complex (MHC) II genotypes and the TNF alpha promoter polymorphism were determined by PCR method. We examined 69 type 1 diabetic and 42 LADA patients. As control samples of 336 cadaver kidney donors and 138 volunteers were used. RESULTS: Both type 1 diabetes mellitus and LADA were positively associated with the DRB1*04-DQB1*0302 (DR4/DQ8) haplotype (P=0.00001, and P=0.0005, respectively), and negatively associated with the DRB1*11-DQB1*0301 (DR11/DQ7) haplotype (P=0.00006, and P=0.007, respectively) compared with control population. There were differences between the two disease entities in the frequency of the DRB1*03-DQB1*02 (DR3/DQ2) haplotype (P=0.00008 vs. P=0.177) compared with control group. The presence of the TNF2 allele was significantly lower in LADA than type I diabetes (P=0.022) or control group (P=0.017). CONCLUSION: Our findings indicate that there are marked differences in the genetic background of type 1 diabetes and LADA. The low presence of TNF2 allele (known to be associated with high amount of TNF alpha production) in LADA could be one of the factors responsible for the relatively slow progression.

Adult↗

PubMed2002

[Genomic approach to allergic diseases: present and future perspectives].

The rapid advances in genomic research have a major impact on biomedical sciences. In this review the authors summarize the current results of the genomic investigation of allergic diseases. From a genetic point of view allergy is multifactorial, which means that the susceptibility to the disease is determined by interactions between multiple genes, and involve important nongenetic factors such as the environment for their expression. There are two widespread methods for searching for disease susceptibility genes in allergy: (1) genome-wide search and (2) candidate gene association studies. Until now five groups have completed genome-wide searches for asthma, and almost 500 genetic linkage and association studies have reported more than 500 atopy and asthma loci throughout the genome. In this review we selected those results, which were consistently confirmed by several independent studies, or appeared particularly important, or interesting. On the basis of this, 9 chromosome regions can be associated with the susceptibility to allergic diseases: 2q, 5q31-q33, 6p21.3, 7q31, 11q13, 12q14.3-q24.31, 14q11.2-q13, 16p21, 17q11.2. According to the results of the human genome programs, and association studies, the authors discuss the possible roles of candidate genes found in these loci in the pathomechanism of allergy. Besides, the authors summarize briefly the results of pharmacogenomics, and animal linkage and genetics studies related to allergy.

Animals↗

PubMed2002

Association of plasma lipid levels with apolipoprotein E polymorphism in Type 2 diabetes.

OBJECTIVE: To evaluate the distribution of apolipoprotein E polymorphism in patients with Type 2 diabetes and their impact on plasma lipid levels. SUBJECTS: Unrelated Type 2 diabetic patients (n = 298) treated by diet and sulfonylurea and not receiving lipid-lowering regimens, elderly (n = 98) and young (n = 101)unrelated healthy control subjects in Hungary. METHODS: Apolipoprotein E genotypes were identified by PCR amplification and subsequent restriction endonuclease digestion. RESULTS: The distribution of the most frequent genotypes in the diabetes group was E2/3 8.7%, E3/3 78.2%, E3/4 12.8%, in the elderly group E2/3 9.2%, E3/3 78.6%, E3/4 12.2% and in the young group E2/3 11.9%, E3/3 62.4%, E3/4 24.8%. The frequencies of allele e4 in the diabetes and in the elderly control group were significantly lower than in the young control group (both P < 0.05). Associations were found between the e4 allele and increased triglyceride level in the diabetes group, the e2 allele and decreased total cholesterol and LDL-cholesterol levels both in the elderly and young control groups (both P < 0.01). CONCLUSION: The lower frequency of allele e4 in both the elderly and diabetes groups, may be explained by an increased morbidity and mortality in middle-aged carriers of apo e4 allele. The increased risk of e4 carriers in Type 2 diabetes may be partly mediated by a higher triglyceride level.

Adult↗

PubMed2002

Bone marrow-derived mast cell differentiation is strongly reduced in histidine decarboxylase knockout, histamine-free mice.

Mast cells are differentiated in vitro from bone marrow precursors. In this study the development of bone marrow-derived mast cells was examined from histidine decarboxylase deficient (HDC-/-) and wild-type mice in the presence of IL-3. The number of non-adherent, tryptase- and c-kit-positive mast cells in bone marrow-derived cultures of HDC(-/-) mice was decreased compared to that of wild-type (HDC+/+) animals, but within the tryptase- and c-kit-positive cells there was no difference in the expression intensity of both markers between the two groups. Furthermore, less serine proteases mMCP5, mMCP6 and FcepsilonRIalpha mRNA were detected in bone marrow-derived cell cultures originating from HDC-/- mice. Antigen-provoked degranulation through high-affinity FcepsilonI receptor was also lower in HDC-/- mice. The colony assays in semisolid medium yielded a significantly lower ratio of mixed colonies and higher proportion of macrophage colonies from HDC-/- mice-derived bone marrow compared to the wild-type. In the course of the differentiation of HDC-/- --derived mast cells exogenously added histamine is unable to substitute the endogenously missing histamine. Concordantly, alpha-fluoromethyl-histamine, the specific inhibitor of HDC, revealed only a marginal inhibition on the differentiation of tryptase-positive mast cells from wild-type mice. These findings suggest that the effect of histamine on the IL-3-dependent development of bone marrow-derived mast cell differentiation during the early period is crucial and irreplaceable.

Animals↗

PubMed2002

The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma (Gypsy) patients across Europe.

Galactokinase deficiency is an inborn error of metabolism that, if untreated, results in the development of cataracts in the first weeks of life. The disorder is rare worldwide, but has a high incidence among the Roma (Gypsies). In 1999, we reported the founder Romani mutation, P28T, identified in affected families from Bulgaria. Subsequent studies have detected the same mutation in Romani patients from different European countries. The screening of 803 unrelated control individuals of Romani ethnicity from Bulgaria, Hungary, and Spain has shown an overall carrier rate of 1:47 and an expected incidence of affected births about 1:10,000. Using disease haplotype analysis, the age of the P28T mutation was estimated at 750 y, preceding the splits of the proto-Roma into the numerous populations resident in Europe today. The findings suggest that the mutation has spread with the early diaspora of the Roma throughout Europe. Superimposed on this old distribution pattern is the new migration wave of the last decade, with large numbers of Roma moving to Western Europe as a result of the economic changes in the East and the wars in former Yugoslavia. The changing demographic pattern of Romani minorities can be expected to lead to a homogenization of the incidence of "private" Romani disorders and founder mutations. The P28T mutation is thus likely to account for a high proportion of galactokinase deficiency cases across Europe. Mutation-based pilot newborn screening programs would provide current incidence figures and help to design long-term prevention of infantile cataracts due to galactokinase deficiency.

Amino Acid Substitution↗

PubMed2002

Histamine genomics in silico: polymorphisms of the human genes involved in the synthesis, action and degradation of histamine.

BACKGROUND: Histamine is a ubiquitous biogenic amine involved in the regulation of numerous basic physiological and pathophysiological processes. The DNA sequences of the genes encoding proteins (enzymes and receptors) that participate in the synthesis, degradation and cellular binding of histamine are already identified. OBJECTIVE: We analyzed the in silico available human sequences to find genetic polymorphisms in histamine-related genes (L-histidine decarboxylase, histamine receptors, histamine N-methyl transferase and diamine-oxidase), and compared these data with findings concerning structure-function relationships in order to get information about the possible pathophysiological relevance of these polymorphisms. METHODS: Sequence analysis was performed at the National Center for Biotechnology Information Database. The search tool BLAST was applied. RESULTS: Several sequence variations were found, and it is conceivable that some of these genetic polymorphisms may be related to various pathological conditions. Among sequence variations, variants with no amino acid change, variants resulting in amino acid alterations, and many nucleotide changes involving non-coding sequences were revealed. CONCLUSIONS: Histamine genomics may provide a new tool for medical prediction and drug design in the future.

Histamine↗