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Andrew J Mungall

Publications and source records attributed to Andrew J Mungall.

5 recordsLinked to original sources
PubMed2002

Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors.

The common fragile site FRA6F, located at 6q21, is an extended region of about 1200 kb, with two hot spots of breakage each spanning about 200 kb. Transcription mapping of the FRA6F region identified 19 known genes, 10 within the FRA6F interval and nine in a proximal or distal position. The nucleotide sequence of FRA6F is rich in repetitive elements (LINE1 and LINE2, Alu, MIR, MER and endogenous retroviral sequences) as well as in matrix attachment regions (MARs), and shows several DNA segments with increased helix flexibility. We found that tight clusters of stem-loop structures were localized exclusively in the two regions with greater frequency of breakage. Chromosomal instability at FRA6F probably depends on a complex interaction of different factors, involving regions of greater DNA flexibility and MARs. We propose an additional mechanism of fragility at FRA6F, based on stem-loop structures which may cause delay or arrest in DNA replication. A senescence gene likely maps within FRA6F, as suggested by detection of deletion and translocation breakpoints involving this fragile site in immortal human-mouse cell hybrids and in SV40-immortalized human fibroblasts containing a human chromosome 6 deleted at q21. Deletion breakpoints within FRA6F are common in several types of human leukemias and solid tumors, suggesting the presence of a tumor suppressor gene in the region. Moreover, a gene associated to hereditary schizophrenia maps within FRA6F. Therefore, FRA6F may represent a landmark for the identification and cloning of genes involved in senescence, leukemia, cancer and schizophrenia.

Aging↗
PubMed2002

The human homologue of unc-93 maps to chromosome 6q27 - characterisation and analysis in sporadic epithelial ovarian cancer.

BACKGROUND: In sporadic ovarian cancer, we have previously reported allele loss at D6S193 (62%) on chromosome 6q27, which suggested the presence of a putative tumour suppressor gene. Based on our data and that from another group, the minimal region of allele loss was between D6S264 and D6S149 (7.4 cM). To identify the putative tumour suppressor gene, we established a physical map initially with YACs and subsequently with PACs/BACs from D6S264 to D6S149. To accelerate the identification of genes, we sequenced the entire contig of approximately 1.1 Mb. Seven genes were identified within the region of allele loss between D6S264 and D6S149. RESULTS: The human homologue of unc-93 (UNC93A) in C. elegans was identified to be within the interval of allele loss centromeric to D6S149. This gene is 24.5 kb and comprises of 8 exons. There are two transcripts with the shorter one due to splicing out of exon 4. It is expressed in testis, small intestine, spleen, prostate, and ovary. In a panel of 8 ovarian cancer cell lines, UNC93A expression was detected by RT-PCR which identified the two transcripts in 2/8 cell lines. The entire coding sequence was examined for mutations in a panel of ovarian tumours and ovarian cancer cell lines. Mutations were identified in exons 1, 3, 4, 5, 6 and 8. Only 3 mutations were identified specifically in the tumour. These included a c.452G>A (W151X) mutation in exon 3, c.676C>T (R226X) in exon 5 and c.1225G>A(V409I) mutation in exon 8. However, the mutations in exon 3 and 5 were also present in 6% and 2% of the normal population respectively. The UNC93A cDNA was shown to express at the cell membrane and encodes for a protein of 60 kDa. CONCLUSIONS: These results suggest that no evidence for UNC93A as a tumour suppressor gene in sporadic ovarian cancer has been identified and further research is required to evaluate its normal function and role in the pathogenesis of ovarian cancer.

Amino Acid Sequence↗
PubMed2002

Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer.

We have previously shown a high frequency of allele loss at D6S193 (62%) on chromosomal arm 6q27 in ovarian tumours and mapped the minimal region of allele loss between D6S297 and D6S264 (3 cM). We isolated and mapped a single non-chimaeric YAC (17IA12, 260-280 kb) containing D6S193 and D6S297. A further extended bacterial contig (between D6S264 and D6S149) has been established using PACs and BACs and a transcript map has been established. We have mapped six new markers to the YAC; three of them are ESTs (WI-15078, WI-8751, and TCP10). We have isolated three cDNA clones of EST WI-15078 and one clone contains a complete open reading frame. The sequence shows homology to a new member of the ribonuclease family. The other two clones are splice variants of this new gene. The gene is expressed ubiquitously in normal tissues. It is expressed in 4/8 ovarian cancer cell lines by Northern analysis. The gene encodes for a 40 kDa protein. Direct sequencing of the gene in all the eight ovarian cancer cell lines did not identify any mutations. Clonogenic assays were performed by transfecting the full-length gene in to ovarian cancer cell lines and no suppression of growth was observed.

Amino Acid Sequence↗
PubMed2002

Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.

PURPOSE: Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes. METHODS: Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region. RESULTS: Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed. CONCLUSIONS: These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.

Base Sequence↗