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Z Urbán

Publications and source records attributed to Z Urbán.

18 recordsLinked to original sources
PubMed2006

Morphology and synaptic input of substance P receptor-immunoreactive interneurons in control and epileptic human hippocampus.

Substance P (SP) is known to be a peptide that facilitates epileptic activity of principal cells in the hippocampus. Paradoxically, in other models, it was found to be protective against seizures by activating substance P receptor (SPR)-expressing interneurons. Thus, these cells appear to play an important role in the generation and regulation of epileptic seizures. The number, distribution, morphological features and input characteristics of SPR-immunoreactive cells were analyzed in surgically removed hippocampi of 28 temporal lobe epileptic patients and eight control hippocampi in order to examine their changes in epileptic tissues. SPR is expressed in a subset of inhibitory cells in the control human hippocampus, they are multipolar interneurons with smooth dendrites, present in all hippocampal subfields. This cell population is considerably different from SPR-positive cells of the rat hippocampus. The CA1 (cornu Ammonis subfield 1) region was chosen for the detailed morphological analysis of the SPR-immunoreactive cells because of its extreme vulnerability in epilepsy. The presence of various neurochemical markers identifies functionally distinct interneuron types, such as those responsible for perisomatic, dendritic or interneuron-selective inhibition. We found considerable colocalization of SPR with calbindin but not with parvalbumin, calretinin, cholecystokinin and somatostatin, therefore we suppose that SPR-positive cells participate mainly in dendritic inhibition. In the non-sclerotic CA1 region they are mainly preserved, whereas their number is decreased in the sclerotic cases. In the epileptic samples their morphology is considerably altered, they possessed more dendritic branches, which often became beaded. Analyses of synaptic coverage revealed that the ratio of symmetric synaptic input of SPR-immunoreactive cells has increased in epileptic samples. Our results suggest that SPR-positive cells are preserved while principal cells are present in the CA1 region, but show reactive changes in epilepsy including intense branching and growth of their dendritic arborization.

Adult↗
PubMed2004

Association of polymorphisms and haplotypes in the elastin gene in Dutch patients with sporadic aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: A locus containing the elastin gene has been linked to familial intracranial aneurysms in 2 distinct populations. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes of SNPs in the elastin gene with the occurrence of subarachnoid hemorrhage (SAH) from sporadic aneurysms in the Netherlands. METHODS: We genotyped 167 SAH patients and 167 matching controls for 18 exonic and intronic SNPs in the elastin gene. A Bonferroni correction was applied for multiple comparisons with all novel associations, with a correction factor derived from the number of SNPs tested (P value after Bonferroni correction [P(corr)]). RESULTS: SAH was statistically significant associated with an SNP in exon 22 of the elastin gene (minor allele frequency was 0.000 in patients and 0.028 in controls; odds ratio [OR], 0.0; 95% CI, 0.0 to 0.7; P=0.004; P(corr)=0.05) and possibly with an SNP in intron 5 (minor allele frequency was 0.062 in patients and 0.128 in controls; OR, 0.5; 95% CI, 0.2 to 0.8; P=0.007; P(corr)=0.08). Haplotypes of intron 5/exon 22 (P(corr)=0.002), intron 4/exon 22 (P(corr)=0.02), and intron 4/intron 5/exon 22 (P=9.0x10(-9)) were also associated with aneurysmal SAH. CONCLUSIONS: Variants and haplotypes within the elastin gene are associated with the risk of sporadic SAH in Dutch patients. Gradual increase of statistical power with the inclusion of 2 or 3 SNPs in the studied haplotypes supports the validity of our conclusion that the elastin gene is a susceptibility locus for SAH.

Alleles↗
PubMed2002

Calretinin-containing interneurons innervate both principal cells and interneurons in the CA1 region of the human hippocampus.

Hippocampal interneurons consist of functionally diverse cell types, most of them target the dendrites or perisomatic region of pyramidal cells with a few exceptions, like the calretinin-containing cells in the rat: they selectively innervate other interneurons. However, no electron microscopic data are available about the synaptic connections of calretinin-immunoreactive neurons in the human hippocampus. We aimed to provide these data to establish whether interneuron-selective interneurons indeed represent an essential feature of hippocampal circuits across distant species. Two types of calretinin-immunostained terminals were found in the CA1 region: one of them presumably derived from the thalamic reuniens nucleus, and established asymmetric synapses on dendrites and spines. The other type originating from local interneurons formed symmetric synapses on both pyramidal and interneuron dendrites. Distribution of postsynaptic targets showed that 26.8% of the targets were CR-positive interneuron dendrites, and 25.2% proved to be proximal pyramidal dendrites. CR-negative interneuron dendrites were also contacted (12.4%). Small caliber postsynaptic dendrites were not classified (28%). Somata were rarely contacted (7.6%). The present data suggest that calretinin-positive boutons do show a preference for other interneurons, but a considerable proportion of the targets are pyramidal cells. We propose that interneuron-selective inhibitory cells exist in the human Ammon's horn, and boutons innervating pyramidal cells derive from another cell type that might not exist in rodents.

Adult↗
PubMed2001

Supravalvular aortic stenosis: genetic and molecular dissection of a complex mutation in the elastin gene.

We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency.

Alleles↗
PubMed2001

Differences by sex in cardiovascular disease in Williams syndrome.

OBJECTIVE: To analyze the incidence and severity of cardiovascular disease in patients with Williams syndrome (WS) and to identify factors contributing to its variable expression. METHODS: Clinical data on patients with WS were collected from several WS centers. Elastin gene deletions were confirmed in all patients. Age at diagnosis, growth data, and cardiovascular diagnoses were recorded retrospectively. Cardiac diagnoses were made on the basis of echocardiographic data. The severity of supravalvular aortic stenosis was recorded by using a 4-step scale (none, mild, moderate, severe). RESULTS: Statistical analysis of the data revealed that the severity of both supravalvular aortic stenosis and total cardiovascular disease was significantly greater in male patients than female patients (P <.002 and P <.002, respectively; Kruskal-Wallis rank-sum test). This difference was not accounted for by differences in height, weight, body mass index, or head circumference. The clinical diagnosis of WS was made at a significantly younger age in male patients (P <.01, Student t test). Earlier diagnosis was partly because of increased incidence and severity of cardiovascular disease. Another determinant of early diagnosis was low body mass index. CONCLUSION: Penetrance and severity of the elastin arteriopathy in patients with WS is affected by sex. We hypothesize that differences by sex in arterial stenoses may be related to prenatal hormonal effects. Future epidemiologic and in vitro studies may provide additional insight into the pathogenetic mechanisms of these observed differences.

Adolescent↗
PubMed2000

Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay.

We have used single-strand conformation and heteroduplex analyses of genomic amplimers to identify point mutations within the elastin gene (ELN) in patients with non-syndromic supravalvular aortic stenosis (SVAS) from a total of eight unrelated families. Six novel point mutations were identified. We have collected detailed clinical information on mutation carriers and demonstrated significant non-penetrance in some of the families. Together with the new mutations described here, 14 point mutations have been reported in SVAS patients, and 10 of these result in premature stop codons (PTCs). We have analyzed the expression of ELN alleles in skin fibroblasts from one SVAS patient and shown that PTC mutations indeed result in selective elimination of mutant transcripts. Inhibition of the nonsense-mediated decay mechanism by cycloheximide resulted in the stabilization of mutant elastin mRNA. Allelic inactivation by the ELN mutation in this patient led to an overall decrease of the steady state levels of elastin mRNA. Finally, we have demonstrated reduced synthesis and secretion of tropoelastin by skin fibroblasts from the same SVAS patient. We conclude that PTC mutations in ELN result in nonsense-mediated decay of mutant mRNA in this patient. Given the predominance of PTC mutations in SVAS, we suggest that functional haploinsufficiency may be a pathomechanism underlying most cases of non-syndromic SVAS.

Adolescent↗
PubMed2000

Genetic disorders of the elastic fiber system.

Over the last decade, a considerable amount of new information has emerged describing the protein components of elastic fibers. It is now evident that elastic fibers are complex extracellular matrix polymers, composed of at least 19 different proteins that comprise both the microfibrillar and the amorphous components of elastic fibers. Mutations in three of the genes encoding the most abundant of these elastic fiber proteins result in a broad spectrum of elastic tissue phenotypes, ranging from skeletal and skin abnormalities to vascular and ocular defects. The following disorders will be discussed in this review: supravalvular aortic stenosis; Williams-Beuren syndrome; cutis laxa; Marfan syndrome; ectopia lentis; familial thoracic aortic aneurysms and dissections; MASS syndrome; isolated skeletal features of Marfan syndrome; Shprintzen-Goldberg syndrome; and congenital contractural arachnodactyly.

Aortic Stenosis, Supravalvular↗
PubMed1999

Supravalvular aortic stenosis: a splice site mutation within the elastin gene results in reduced expression of two aberrantly spliced transcripts.

We have screened the elastin gene for mutations responsible for supravalvular aortic stenosis (SVAS) in two large, independently collected families with isolated (nonsyndromic) SVAS. By single-strand conformation polymorphism and heteroduplex analysis, we have identified a C to G transversion within the acceptor splice site of exon 16 in SVAS patients from both families. This mutation segregates in both families with high penetrance of SVAS, and all affected individuals carry the mutation. Haplotype analysis by using closely linked polymorphisms, including a previously unreported BfaI restriction fragment length polymorphism within the 3'-UTR of the elastin gene, indicates that the mutations found in the two apparently non-overlapping kindreds are identical by descent. To study the effect of the mutation on the expression of the mutant allele, we have established a primary skin fibroblast culture from one of the affected individuals. Reverse transcription/polymerase chain reaction analysis of elastin mRNA species indicates that the mutation results in two abnormal elastin mRNA species. One mutant elastin mRNA is generated by the activation of a cryptic splice site that lies within intron 15 and that adds 44 bp of intronic sequence to the sequence encoded by exon 16. This insertion creates a frame shift that results in a 59-amino-acid-long abnormal protein sequence and leads to a termination codon in the mRNA sequence encoded by exon 17. The smaller abnormal mRNA species arises as a consequence of the skipping of exon 16. This study demonstrates, for the first time, the expression of mutant alleles of the elastin gene in patients with isolated SVAS.

Alternative Splicing↗
PubMed1998

A gene-dosage PCR method for the detection of elastin gene deletions in patients with Williams syndrome.

Williams syndrome (WS) is a multisystem developmental disorder associated with microdeletions at 7q11.23 that involve several genes, including the elastin gene. Using genomic DNA from a panel of normal individuals and WS patients with established hemizygosity of the elastin gene locus, we have developed a quantitative polymerase chain reaction (PCR)-based gene-dosage assay that rapidly detects the loss of one allele of the elastin gene. Using this procedure, we also studied a family in which the proband was previously diagnosed with WS and her mother with a balanced 7q translocation [t(7:11)(q34;q13)]. Using DNA isolated from buccal smears obtained from several individuals in this family we were able to establish normal disomy at 7q in all family members except for the proband, in which we established hemizygosity at the elastin gene locus. We were also able to successfully infer normal disomy in an unborn child in this family. The rapid diagnostic procedure described here may have a variety of applications, including fine mapping of deletion breakpoints at 7q11.23 associated with WS.

Adult↗
PubMed1997

[Genetic diagnosis of Williams syndrome].

Williams syndrome is a complex developmental disorder. The major cardiovascular component of Williams syndrome is supravalvular aortic stenosis, a progressive disease that may need surgical repair. Williams syndrome is associated with heterozygous microdeletion in the chromosomal region 7q11.23 encompassing the elastin gene. We have identified a new, highly informative tetranucleotide repeat polymorphism within the human elastin gene. This marker together with other, previously described elastin gene markers was used to show deletion of the elastin gene in nine sporadic Williams syndrome patients from Hungary. Application of polymorphisms within and flanking the elastin gene on chromosome 7 provides a fast, polymerase chain reaction based method for mutational analysis of Williams syndrome patients.

Aortic Valve Stenosis↗
PubMed1996

Structure and the promoter region of the mouse gene encoding the 67-kD form of glutamic acid decarboxylase.

We have cloned and determined the complete structure of the murine gene encoding the 67-kD form of glutamic acid decarboxylase (GAD67), the gamma-aminobutyric acid synthetic enzyme. Its coding region comprises 18 exons spanning 42 kb of genomic DNA. Exon 1 together with 64 bp of exon 2 defines the 5' untranslated region of GAD67 mRNA. Exon 18 specifies the protein's carboxyl terminal and the entire 3' untranslated region. Exons 7/A and 7/B are solely contained in the coding regions of two alternatively spliced bicistronic embryonic mRNAs, which code for the truncated embryonic GAD forms. The promoter region (P1) corresponding to the main group of transcription initiation sites is devoid of TATA and CAAT boxes but has putative binding sites for the transcription factor SP1 and is embedded in a large G + C-rich domain of a CpG island, features shared by the promoters of constitutively expressed housekeeping genes. Primer extension data suggests the existence of additional transcription start sites at 130 bp and 295 bp upstream from the major initiation site that are utilized less frequently in adult brain. The tentative distal promoters (P2 and P3) that correspond to the minor start sites resemble tissue-specific promoters with TATA and CAAT-like boxes. In 1.3 kb of the 5'-upstream region, we identified several putative transcription factor binding sites such as AP2, Hox, E-box, egr-1, and NF-kappaB and putative neuronal-specific regulatory elements, including the neuronal-restrictive silencer element, which may have functional significance in the developmental and tissue-specific expression of the GAD67 gene.

Animals↗
PubMed1975

Cytological changes and antigen capture in chicken spleen during the secondary immune response to homologous and cross-reacting antigens.

It was demonstrated by autoradiography using 125I-labeled antigens that in the secondary response to bovine serum albumin (BSA), a considerable amount of antigen is localizing in the germinal centers (GC) of chicken spleen prior to the onset of antibody production. A similar early antigen capture, although of a lesser degree, was also noted when birds originally immunized with BSA were injected with human serum albumin (HSA) on a second occasion. Early antigen localization in GCs was scarcely demonstrable in the primary response. Since antigen capture requires specific antibodies, it was concluded that the antigen binding cells correspond with B lymphocytes of GCs formed during the primary immune response or with their descendants. On antigenic stimulus, these cells transform to antibody producing cells after one or more mitoses. GCs can therefore be regarded as memory units composed of cells committed to one and the same antigen. Cells of the thymus-system probably play a cooperative role in the antigen-induced formation of GCs.

Animals↗
PubMedDate not supplied

Elastin gene deletions in Williams syndrome patients result in altered deposition of elastic fibers in skin and a subclinical dermal phenotype.

Williams syndrome (WS) is a complex developmental disorder with multisystem involvement known to be the result of a microdeletion in the q11.23 region of chromosome 7. This deletion involves several genes, including the elastin gene. Although elastic fibers are important constituents of skin, little is known about the skin phenotype in WS patients. We have therefore studied the skin of four WS patients in which we've shown the deletion of one copy of the elastin gene. Physical examination and indirect immunofluorescent microscopy of elastin did not detect any major phenotypic or morphologic changes in the skin. We were able, however, to show subtle textural changes in skin and, by electron microscopy, that the amorphous component of elastic fibers in WS patients was consistently reduced when compared to normal controls. These findings indicate that deletion of one copy of the elastin gene results in reduced deposition of elastin in dermal elastic fibers, an altered elastic fiber ultrastructure, and a subclinical dermal phenotype in the children and young adult patients analyzed in this study.

Adult↗