PubMed · 7874160
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P J Willems. 1994. Dynamic mutations hit double figures.. https://doi.org/10.1038/ng1194-213
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The repeat expansion diseases are genetic disorders caused by intergenerational expansions of a specific tandem DNA repeat. These disorders range from mildly to severely debilitating or fatal, and all have limited treatment options. How expansion occurs and causes disease is only now beginning to be understood. Efforts to model expansion in mice have so far met with only limited success, perhaps due to a requirement for specific cis- or trans-acting factors. In vitro studies and data from bacteria and yeast suggest that in addition to secondary structures formed by the repeats, components of the DNA replication and recombination machinery are important determinants of instability. The consequences of expansion differ depending on where in the gene the repeat tract is located, and range from reduction of transcription initiation to protein toxicity. Recent advances are beginning to make rational approaches to the development of therapies possible.
Fanconi anemia is a rare autosomal recessive disorder which is characterized with chromosomal fragility and hypersensitivity to DNA cross-link agents. There are large variability in phenotype even among patients of single family. Therefore, diagnosis depends solely on hypersensitivity to DNA cross-link agents. At present at least 8 complement groups are known and 3 genes, FANCA, FANCC and FANCG, have been cloned. There is controversies concerning intracellular localization and interaction between these genes. Although the mechanism of the final effect of products of these genes leading to Fanconi anemia phenotype, chromosomal fragility and ultimately development of cancers is not fully understand, increasing evidence shows that gene products seems to work to prevent oxygen injury by reactive oxygen species rather than repair of DNA injury.
Detailed deletion mapping of chromosome 6q sequences in invasive ovarian tumors have implicated several broad regions involving 6q14-16, 6q21-23, 6q25-26, and the telomeric portion in band 6q27 as regions of frequent loss in this malignancy. In order to define regions of loss involved in the development of ovarian cancer, we used 23 polymorphic markers on 6q to examine allelic loss in 25 high-grade, late stage ovarian tumors. Four non-overlapping deletion regions were observed: (1) at 6q21-22.3 (D6S301-D6S292); (2) within a 1 cM region at 23.2-23.3 between markers D6S978-D6S1637 (at D6S311); (3) at 6q26 (between markers D6S411-D6S1277) and (4) at 6q27 with the markers D6S297 and D6S193. The highest region of loss was observed with marker D6S311 (lost in 17 of 19 informative cases, 89%) in 6q23.3, followed by D6S977 and D6S1637 (71 and 55%, respectively). The average fractional allele loss in the high-grade tumors was around 35%. Previous reports have shown 6q27 as the region of most frequent loss in invasive ovarian cancer. However, our results indicate a novel region in 6q23.3 (spanning less than 500 Kb distance between the markers) with the highest loss, implicating this region of chromosome 6q to harbor a putative tumor suppressor gene involved in the development of invasive epithelial ovarian cancer.