Analysis of Expressed Sequence Tags Mapping to the Critical Region of the 5q- Syndrome

Strickson, Amanda Jane (2002). Analysis of Expressed Sequence Tags Mapping to the Critical Region of the 5q- Syndrome. PhD thesis The Open University.



The 5q- syndrome is a myelodysplastic syndrome characterised by a macrocytic anaemia, hypolobulated megakaryocytes, a low risk of transformation to AML, and a 5q- chromosome as the sole karyotypic abnormality. The approximate 5Mb critical region of gene loss of the 5q- syndrome has been defined in two patients with the 5q- syndrome at 5q31-q33, flanked by the genes for FGF1 and IL12ß.

The frequent loss of genetic material from the long arm of chromosome 5 in association with a malignancy has led to the hypothesis that, by analogy with other malignancies characterised by genetic loss, the 5q- syndrome is caused by loss of function of a gene with tumour suppressor activity.

A transcript map of the 5q- syndrome critical region was generated with the aim of identifying the putative tumour suppressor gene associated with this disease. The expressed sequence tag (EST) database, db(EST) was used to isolate novel coding sequences mapping to the critical region of gene loss. Ten novel coding sequences (C5orf4, AF010242, AF156165, Cdy-17a06, Bda-87b11 195312, 4885953 / 143772,120101,195971, and 199067) were localised to the YAC contig spanning the critical region at 5g31-q33. The ten cDNA clones were sequenced, and overlapping clones were identified and sequenced in order to generate complete or partial coding sequences. This included the cloning of novel gene, C5orf4, and the identification of the human synaptopodin and dynactin p62 genes. In addition, the human homologues of the Drosophila melanogaster RMSA-1 and Saccharomyces cerevisiae CDC60 genes, and two known human genes (PP2A and HAH1) were localised to the critical region. Expression in human peripheral blood leukocytes and CD34+ progenitor cells was investigated for each known and novel gene. Genomic localisation, expression patterns and predicted function would suggest these known and novel genes represent putative tumour suppressor genes.

Mutation studies were carried out on six known, and two novel candidate genes mapping to the narrowed 1.5Mb critical region of gene loss at 5g31.3-q32. No mutations were found in the coding regions/exons of these genes, suggesting they are not involved in the pathogenesis of the 5q- syndrome.

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