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Biomedical subjects

A M Frischauf

Publications and source records attributed to A M Frischauf.

At least 37 records · Page 2Linked to original sources
PubMed1996

Structural motifs of the PKD1 protein.

The complete sequence of the polycystic kidney disease gene (PKD1) and its transcript have been described. The predicted protein is not a member of a previously described gene family, but contains several structural motifs that are present in proteins of known function. Most of these domains are present in the extracellular parts of proteins involved in interactions with other proteins and carbohydrates. The PKD1 gene product also contains potential transmembrane sequences. The molecule is likely to be involved in cell-cell or cell-matrix interactions, which is consistent with the different manifestations of polycystic kidney disease.

Genes↗
PubMed1996

A high-resolution radiation hybrid map of the region surrounding the Gorlin syndrome gene.

We have constructed a set of hybrid cell lines by irradiation of GM 64063 (human chromosome 9q only on hamster background) and fusion to hamster A23 Tk-, 109 independent lines were tested by PCR with 24 markers from chromosome 9q. The marker density is highest in the 9q22.3-q31 region containing the gene for Gorlin syndrome, a familial predisposition to basal cell carcinoma. The resolution of our map in this region is significantly higher than other published maps and will enable accurate placing of new markers and genes within the 9q22.3-q3.1 region. This is important since yeast artificial chromosomes from the region are likely to contain deletions.

Animals↗
PubMed1995

Mapping around the Fused locus on mouse chromosome 17.

We have established a high-resolution genetic map of the region surrounding the Fused locus as a first step towards the molecular identification and analysis of this gene. The candidate region has been covered to a large extent by YAC and P1 contigs, and has been partly characterized by pulsed-field gel analysis.

Animals↗
PubMed1995

Haplotype analysis in autosomal dominant polycystic kidney disease.

Haplotype analysis was performed in 35 autosomal dominant polycystic kidney disease (ADPKD) families typed with 13 markers close to the PKD1 locus. The identification of recombinants close to the PKD1 gene on chromosome 16p indicates that PKD1 lies between CMM65 distally and 26-6 proximally. In addition, three unlinked (PKD2) families and two families with potential new mutation were identified.

Adult↗
PubMed1994

A novel cyclin gene (CCNF) in the region of the polycystic kidney disease gene (PKD1).

The major locus for autosomal dominant polycystic kidney disease (PKD1) is located in a gene-rich region on chromosome 16p13.3. Recently the identification of the gene responsible for PKD1 has been described. While searching for candidate genes in this region, we isolated a new member of the cyclin family. We have characterized the transcript by sequencing, determination of the exon intron boundaries, and Northern blot analysis. Cyclin F is related to A- and B-type cyclins by sequence, but its function is unknown.

Amino Acid Sequence↗
PubMed1994

Genetic heterogeneity in familial malignant melanoma.

Following reports of linkage to chromosome 9p in families with malignant melanoma, we have been studying a series of UK families. Six families were selected with three or more cases of malignant melanoma. We have used a total of twelve markers mapping in the interval 9p13-p23 and constructed a set of haplotypes to study the inheritance of the disease chromosome. Of the six families, three were consistent with linkage to the short arm of 9, although their limited size precluded confirmation of linkage. One family was clearly unlinked, one family was either unlinked, or contains a sporadic case, or delimits the location of the melanoma gene, and one family was essentially uninformative. This is strong evidence for genetic heterogeneity in families with the malignant melanoma phenotype. We have also sequenced exon 2 of the recently identified candidate tumour suppressor gene, p16, in six individuals and found no evidence for germline mutations in this region of the p16 gene in our families with inherited malignant melanoma.

Adolescent↗
PubMed1993

A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13.

We have constructed a contig of non-chimaeric yeast artificial chromosomes (YACs) across the candidate region for childhood autosomal recessive spinal muscular atrophy (SMA) in 5q13. A novel microsatellite reduces the candidate region to approximately 400kb of DNA distal to D5S435. The candidate region contains blocks of chromosome 5 specific repeats which have copies on 5p as well as elsewhere on 5q. Restriction mapping of the YACs reveals at least one CpG island in the SMA gene region. The YAC maps indicate that the contig contains minimal rearrangements or deletions. The data show the value of screening several YAC libraries simultaneously in order to construct a set of overlapping sequences suitable for candidate gene searches and direct genomic sequencing.

Base Sequence↗
PubMed1993

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3.

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective conformation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome.

Chromosome Deletion↗
PubMed1992

Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.

Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.

Adenomatous Polyposis Coli↗
PubMed1992

Construction of a map of chromosome 16 by using radiation hybrids.

A human-hamster cell hybrid carrying a single copy of chromosome 16 as the only human genetic material was irradiated with a single dose of gamma-rays (7000 rads; 1 rad = 0.01 Gy) and then fused with a thymidine kinase-deficient hamster cell line (RJKM) to generate radiation hybrids retaining unselected fragments of this human chromosome. In two experiments, 223 hybrids were isolated in hypoxanthine/aminopterine/thymidine (HAT) medium and screened with 38 DNA probes, corresponding to anonymous DNA or gene sequences localized on chromosome 16. The most likely order and location of the 38 DNA sequences were established by multiple pairwise analysis and scaled to estimate physical distance in megabases. The order and the distances thus obtained are mostly consistent with available data on genetic and physical mapping of these markers, illustrating the usefulness of radiation hybrids for mapping.

Chromosome Mapping↗
PubMed1992

Radiation hybrid map spanning the Huntington disease gene region of chromosome 4.

Radiation hybrid (RH) mapping was used to construct a map of 11 markers in the distal 4 Mb of the short arm of chromosome 4, the region containing the Huntington disease gene. Two different methods for deriving the order of the markers were compared and both arrived at the same order as being the most likely. This order is also consistent with both the physical map constructed using pulsed-field gel electrophoresis (PFGE) and the meiotic linkage map. Comparing the RH map to the map determined by PFGE provided the means to equate RH map units (centirays) with actual physical distance in kilobases of DNA. In addition, a simple procedure for reducing the complexity of human DNA in radiation hybrids is described. One cell line isolated using this procedure contains, as its only human DNA, approximately 2 Mb surrounding the Huntington disease gene.

Chromosome Mapping↗
PubMed1992

Human-mouse homologies in the region of the polycystic kidney disease gene (PKD1).

Autosomal dominant polycystic kidney disease (PKD1) is linked to the alpha-globin locus near the telomere of chromosome 16p. We established the existence of a conserved linkage group in mouse by mapping conserved sequences and cDNAs from the region surrounding the PKD1 gene in the mouse genome. Results obtained with the BXD recombinant strain system and somatic cell hybrids show the homologous region to be located on mouse chromosome 17 near the globin pseudogene Hba-ps4, an unprocessed alpha-like globin gene. The markers we mapped are widely distributed over the region known to contain the PKD1 gene, and it is therefore likely that the mouse homologue of PKD1 is also located on mouse chromosome 17.

Animals↗
PubMed1992

The gene for autosomal dominant polycystic kidney disease lies in a 750-kb CpG-rich region.

PKD1, the locus most commonly affected by mutations that produce autosomal dominant polycystic kidney disease (ADPKD), has previously been localized to chromosome 16p13.3. Since no cytogenetic abnormalities have been found in association with ADPKD, flanking genetic markers have been required to define an interval--the PKD1 region--that contains the PKD1 gene. In this report we demonstrate, through the construction of a long-range restriction map that links the flanking genetic markers GGG1 (D16S84) and 26.6PROX (D16S125), that the PKD1 gene lies within an extremely CpG-rich 750-kb segment of chromosome 16p13.3. Approximately 90% of this region has been cloned in three extensive cosmid/bacteriophage contigs. The cloned DNA is a valuable resource for identifying new closer flanking genetic markers and for isolating candidate genes from the region.

Chromosomes, Human, Pair 16↗
PubMed1992

Assay by polymerase chain reaction (PCR) of multi-allele polymorphisms in the Huntington's disease region of chromosome 4.

The Huntington's disease-linked D4S115 marker has been converted from a DNA blot assay to a more sensitive and rapid polymerase chain reaction (PCR) assay. PCR amplification of a tandem repeat at D4S115 revealed 7 allelic fragments, ranging in size from approximately 610 to 915 bp, differing in their apparent copy number of a approximately 55 bp core repeat. This repeat unit differs strikingly in sequence from the repeat units of other multi-allele markers from chromosome region 4p 16.3, arguing that the VNTR (Variable Number of Tandem Repeats) loci clustered in this region did not arise from a common ancestral sequence. The D4S115 marker can be assayed simultaneously with PCR products from D4S125, D4S95 and D4S43 on a single agarose gel, providing a rapid scan for successful amplification of these difficult-to-assay VNTRs, and for inheritance of the entire candidate Huntington's disease region. This approach should help to increase the speed, informativeness and accuracy of presymptomatic and prenatal linkage testing in this devastating disorder.

Alleles↗