Search PubMed⌕ Search

Biomedical subjects

M Gessler

Publications and source records attributed to M Gessler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Allele loss in Wilms tumors of chromosome arms 11q, 16q, and 22q correlate with clinicopathological parameters.

An extended analysis for loss of heterozygosity (LOH) on eight chromosomes was conducted in a series of 82 Wilms tumors. Observed rates of allele loss were: 9.5% (1p), 5% (4q), 6% (6p), 3% (7p), 9.8% (11q), 28% (11p15), 13.4% (16q), 8.8% (18p), and 13.8% (22q). Known regions of frequent allele loss on chromosome arms 1p, 11p15, and 16q were analyzed with a series of markers, but their size could not be narrowed down to smaller intervals, making any positional cloning effort difficult. In contrast to most previous studies, several tumors exhibited allele loss for multiple chromosomes, suggesting an important role for genome instability in a subset of tumors. Comparison with clinical data revealed a possible prognostic significance, especially for LOH on chromosome arms 11q and 22q with high frequencies of anaplastic tumors, tumor recurrence, and fatal outcome. Similarly, LOH 16q was associated with anaplastic and recurrent tumors. These markers may be helpful in the future for selecting high-risk tumors for modified therapeutic regimens.

Alleles↗
PubMed1998

Developmental expression patterns of mouse sFRP genes encoding members of the secreted frizzled related protein family.

Development of the metanephric kidney is an experimental model system to analyze interactions between mesenchymal and epithelial cells and mesenchymal-epithelial transition. To study the underlying genetic mechanisms we employed organ culture and differential display PCR to identify genes regulated upon induction of mesenchymal cells. One of the genes found encodes the secreted frizzled related protein 2 (sFRP2) that is upregulated within 2 days of in vitro development. In vivo sFRP2 expression was likewise found in mesenchymal condensates and subsequent epithelial structures. Detailed in situ hybridization analysis revealed sFRP2 expression during development of the eye, brain, neural tube, craniofacial mesenchyme, joints, testis, pancreas and below the epithelia of oesophagus, aorta and ureter where smooth muscles develop. In a comparative analysis transcripts of the related sFRP1 and sFRP4 genes were frequently found in the same tissues as sFRP2 with their expression domains overlapping in some instances, but mutually exclusive in others. While sFRP1 is specifically expressed in the embryonic metanephros, eye, brain, teeth, salivary gland and small intestine, there is only weak expression of sFRP4 except for the developing teeth, eye and salivary gland. The interpretation of the highly specific spatial and temporal expression patterns of sFRP genes will partly depend on a better functional understanding of the interaction between wnt, fz and sFRP family members. Nevertheless, sFRP genes must play quite distinct roles in the morphogenesis of several organ systems.

Animals↗
PubMed1998

Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.

The Wilms' tumor gene WT1 plays a key role in genitourinary development and subsequent normal function. Homozygous mutations of WT1 can be found in approximately 15% of Wilms' tumors. Furthermore, somatic heterozygous loss of WT1 is known to lead to cryptorchidism and hypospadias in males. A much more severe phenotype is seen in patients with Denys-Drash syndrome which results from heterozygous dominant-negative mutations of the gene. Characteristic features are mesangial sclerosis with early kidney failure, varying degrees of gonadal dysgenesis and high risk of Wilms' tumors. Here we show that a related disease, Frasier syndrome, characterized by focal glomerular sclerosis, delayed kidney failure and complete gonadal dysgenesis, is probably caused by specific intronic point mutations of WT1 that preferentially affect a CpG dinucleotide. Disruption of alternative splicing at the exon 9 splice donor site prevents synthesis of the usually more abundant WT1 +KTS isoform from the mutant allele. In contrast to Denys-Drash syndrome, no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo , as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have quite different functions, and the pathology of Frasier syndrome suggests that especially gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform.

Alternative Splicing↗
PubMed1996

Six new polymorphic microsatellite markers used for the integration of genetic and physical maps of human chromosome 7.

We report the isolation and characterization of six new polymorphic dinucleotide repeat microsatellite markers (D7S1491, D7S1492, D7S1493, D7S1494, D7S1495, and D7S1496), their integration into the genetic map of human chromosome 7 by analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees, and their use for integration of physical and genetic maps of this chromosome.

Alleles↗
PubMed1996

Isolation and characterization of Leishmania parasites imported into Switzerland--a retrospective study.

Cases of leishmaniasis imported into Switzerland were diagnosed by culture and/or Giemsa-stained smears. The cultures proved to be positive in 61 of 64 confirmed cases, whereas only 49% of Giemsa-stained smears were positive. Promastigotes were detected on average after 3.6 +/- 2.2 days. A total of 33 different isolates were characterized by isoenzyme analysis and typed as Leishmania infantum (10 cases, mainly from Europe), L. chagasi (1 case, Central America), L. major (12 cases, mainly from Africa), L. braziliensis (7 cases, South and Central America), and L. tropica (1 case, Near East). Two isolates could not be clearly classified. Correlations between species and origin or between species and type of biopsy were as expected.

Adult↗
PubMed1995

An integrated YAC clone contig for the WAGR region on human chromosome 11p13-p14.1.

The WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) deletion region on chromosome 11p13 has been extensively characterized by deletion analysis and long-range restriction mapping. A dense probe set is available for this genomic region, which harbors a number of disease gene loci, some of which still are not cloned. The identification of candidates for these genes would be greatly facilitated by a complete gene map for this chromosomal segment. As an initial step toward this goal, we have isolated the entire region in 58 overlapping YAC clones. The contig spanning 8 Mb from RAG1 to KCNA4 has been assembled by STS and probe content mapping for 76 loci with an average spacing of about 100 kb. A subset of clones has been analyzed by PFG analysis to position these within the known physical map. Common microsatellite markers permit an alignment of the YAC contig with the genetic and radiation hybrid maps of chromosome 11. Ten known genes, some with much more refined map positions, are placed in the contig. The severalfold coverage of 11p13-p14.1 provides a reliable resource for the future development of a complete gene map of this region.

Base Sequence↗
PubMed1995

cDNA sequence, genomic organization, and evolutionary conservation of a novel gene from the WAGR region.

A new gene (239FB) with predominant and differential expression in fetal brain has recently been isolated from a chromosome 11p13-p14 boundary area near FSHB. The corresponding mRNA has an open reading frame of 294 amino acids, a 3' untranslated region of 1247 nucleotides, and a highly GC-rich 5' untranslated region. The coding and 3' UT sequence is specified by 6 exons within nearly 87 kb of isolated genomic locus. The 5' end region of the transcript maps adjacent to the only genomically defined CpG island in a chromosomal subregion that may be associated with part of the mental retardation of some WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome patients. In addition to nucleotide and amino acid similarity to an EST from a normalized infant brain cDNA library, the predicted protein has extensive similarity to two Caenorhabditis elegans polypeptides of, as yet, unknown function. The 239FB locus is, therefore, likely part of a family of genes with two members expressed in human brain. The extensive conservation of the predicted protein suggests a fundamental function of the gene product and will enable evaluation of the role of the 239FB gene in neurogenesis in model organisms.

Amino Acid Sequence↗
PubMed1995

Isolation and characterization of a cosmid contig for the GCPS gene region.

The zinc finger gene GLI3 has been shown to be involved in the embryonal development of the limbs and skull. Mutations in GLI3 lead to the development of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutations extra toes (Xt) and anterior digit deformity (add). The GCPS locus on human chromosome 7p13 has recently been isolated in a yeast artificial chromosome (YAC) contig. Here, we describe the establishment of a cosmid contig that was derived from two of the YAC clones, that spans 550 kb of human DNA, and that includes the GLI3 gene. In this contig, three GCPS translocation breakpoints have been mapped to distinct EcoRI fragments in the 3' half of the gene. In addition, exon-carrying fragments have been identified and the size of the GLI3 gene could be determined as at least 280 kb. The gene is flanked by a CpG island that lies on the 5' side and that is in close proximity to the first exon detected by the cloned GLI3 cDNA. Further upstream, five segments were found that have been conserved between man and mouse. In the mouse, this region has been characterized as the transgene integration site resulting in the add phenotype. Both the CpG island and the conserved regions are probable candidates for a search for GLI3 promoter and control elements.

Abnormalities, Multiple↗
PubMed1995

CpG island clones for chromosome 11p--a resource for mapping and gene identification.

A NotI end fragment library has been constructed for human Chromosome (Chr) 11p. Seventy-two clones were mapped to chromosomal subregions by use of somatic cell hybrids. The clones detect 44 different CpG islands, and we have isolated cosmid contigs for 36 of them. Extrapolation from the known 11p13 NotI restriction map suggests that every second CpG island from 11p containing a Not site is already represented in the clone collection. By sequence analysis all of the 11p13 clones exhibit typical features of CpG islands, and cross-species hybridization has been detected with at least one fragment in most cases. The cosmids serve as valuable linking clones for long-range restriction mapping. They also provide excellent starting material for transcript isolation procedures to identify genes on chromosome 11p associated with developmental anomalies and various tumor types. Several transcribed sequences have already been isolated with some of these clones.

Animals↗
PubMed1995

Identification of optimized target sequences for the GLI3 zinc finger protein.

GLI3 represents an important control gene for development and differentiation of several body structures. Reduction in gene dosage already leads to severe perturbation, especially of limb morphogenesis. The gene encodes a zinc finger protein that likely functions as a transcriptional modulator. Because the five zinc fingers should be capable of recognizing an extended stretch of genomic DNA, we sought to identify sequences bound by GLI3 that may facilitate the search for target genes acting downstream of GLI3. Starting from the nonamer DNA binding sequence of the highly related GLI protein, we employed an oligonucleotide selection protocol to determine an optimized binding sequence for the GLI3 protein. The resulting sequence bound by the GLI3 zinc fingers consists of 16 nucleotides and shows a high degree of similarity to sequences bound by the GLI and tra-1 proteins. Comparison with protein-DNA interactions in the known crystal structure of the GLI-DNA complex suggests relevant interactions of additional amino acids of GLI3 with its target site. The newly identified GLI3 target sequence should prove very useful for both the structural analysis of the protein-DNA complex and the search for genes whose expression is subject to regulation by the GLI3 gene product.

Base Sequence↗
PubMed1995

WT1 expression alters tumorigenicity of the G401 kidney-derived cell line.

Recent studies have implicated a loss of WT1 tumor suppressor gene function in the development of Wilms' tumor (WT). To determine the potential biological consequences of WT1 inactivation in these tumors, we transfected two different splice variant forms of this gene into the pediatric kidney-derived cell line G401. Introduction of this gene caused no detectable effects on the population doubling times of the cell line; proliferative capacity in soft agar was not significantly affected. However, the expression of this gene altered the morphology of the cells in culture and caused a significant suppression of tumorigenicity in the cells. Thus, the expression of WT1 in a pediatric kidney-derived cell line lacking endogenous WT1 production caused demonstrable effects on its in vitro and in vivo growth properties. These data strengthen the concept for a central role for WT1 inactivation in the etiology of this disease.

Animals↗
PubMed1994

An ordered NotI fragment map of human chromosome band 11p15.

An ordered NotI fragment map containing over 60 loci and encompassing approximately 17 Mb has been constructed for human chromosome band 11p15. Forty-two probes, including 11 NotI-linking cosmids, were subregionally mapped to 11p15 using a subset of the J1-deletion hybrids. These and 23 other probes defining loci previously mapped to 11p15 were hybridized to genomic DNA digested with NotI and 5 other infrequently cleaving restriction enzymes and separated by pulsed-field gel electrophoresis. Thirty-nine distinct NotI fragments were detected encompassing approximately 85% of the estimated length of 11p15. The predicted order of the gene loci used is cen-MYOD1-PTH-CALCA-ST5-RBTN1-HPX-HBB-RRM1 -TH/INS/IGF2-H19-CTSD-MUC2-DRD4-HRAS - RNH-tel. This map will allow higher resolution mapping of new 11p15 markers, facilitate positional cloning of disease genes, and provide a framework for the physical mapping of 11p15 in clone contigs.

Cells, Cultured↗
PubMed1994

Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.

Homozygous deletions in Wilms' tumor DNA have been a key step in the identification and isolation of the WT1 gene. Several additional loci are also postulated to contribute to Wilms' tumor formation. To assess the frequency of WT1 alterations we have analyzed the WT1 locus in a panel of 77 Wilms' tumors. Eight tumors showed evidence for large deletions of several hundred or thousand kilobasepairs of DNA, some of which were also cytogenetically detected. Additional intragenic mutations were detected using more sensitive SSCP analyses to scan all 10 WT1 exons. Most of these result in premature stop codons or missense mutations that inactivate the remaining WT1 allele. The overall frequency of WT1 alterations detected with these methods is less than 15%. While some mutations may not be detectable with the methods employed, our results suggest that direct alterations of the WT1 gene are present in only a small fraction of Wilms' tumors. Thus, mutations at other Wilms' tumor loci or disturbance of interactions between these genes likely play an important role in Wilms' tumor development.

Amino Acid Sequence↗
PubMed1994

Isolation of a yeast artificial chromosome contig spanning the Greig cephalopolysyndactyly syndrome (GCPS) gene region.

Disruption of the zinc finger gene GLI3 has been shown to be the cause of Greig cephalopolysyndactyly syndrome (GCPS), at least in some GCPS translocation patients. To characterize this genomic region on human chromosome 7p13, we have isolated a YAC contig of more than 1000 kb including the GLI3 gene. In this contig the gene itself spans at least 200-250 kb. A CpG island is located in the vicinity of the 5' region of the known GLI3 cDNA, implying a potential promoter region.

Abnormalities, Multiple↗
PubMed1994

A WAGR region gene between PAX-6 and FSHB expressed in fetal brain.

Developmental delay or mental retardation is a frequent component of multi-system anomaly syndromes associated with chromosomal deletions. Isolation of genes involved in the mental dysfunction in these disorders should define loci important in brain formation or function. We have identified a highly conserved locus in the distal part of 11p13 that is prominently expressed in fetal brain. Minimal expression is observed in a number of other fetal tissues. The gene maps distal to PAX-6 but proximal to the loci for brain-derived neurotrophic factor (BDNF) and the beta subunit of follicle stimulating hormone (FSHB), within a region previously implicated in the mental retardation component of some WAGR syndrome patients. Within fetal brain, the corresponding transcript is prominent in frontal, motor and primary visual cortex as well as in the caudate-putamen. The characteristics of this gene, including the striking evolutionary conservation at the locus, suggest that the encoded protein may function in brain development.

Blotting, Northern↗