The cause of the disease in two familial and two sporadic cases of aniridia associated with chromosome 11 rearrangements has been analysed. Since the rearrangements apparently leave the PAX6 gene intact, a cosmid contig encompassing <I>PAX6 </I>was assembled and facilitated mapping of the four breakpoints. All were found to lie distal of <I>PAX6</I> at distances of between 20 and 150kb beyond the 3' end of the gene. Phenotypically these patients are indistinguishable from other aniridia cases, suggesting the involvement of PAX6 haploinsufficiency. The site of the most distal breakpoint has been defined by isolating chromosome 11 fragments which cross it. These fragments contain regions of conservation between species and sequencing reveals potential open reading frames, raising questions about the function of the likely gene at this position. A possible position effect mechanism involving disconnection of <I>PAX6</I> from adjacent control elements has been explored. These elements may be locus-specific or more general chromatin organising elements and may be detected by DNaseI hypersensitive site mapping in appropriate cell types. Cell lines which appeared suitable for this purpose have been characterised. An alternative possibility involves disturbance of <I>PAX6 </I>expression by the incoming chromosomal region in each rearrangement, through an inappropriate chromatin conformation or the presence of negative control elements. The detailed physical map generated for the aniridia-associated breakpoint region will allow further exploration of the position effect mechanism. These aniridia-associated rearrangements contribute to a growing list of possible position effect cases in humans and other mammals. Extensive study of position effects in fruit flies and yeast shows that gene inactivation can result from a switch in chromatin environment between euchromatin and heterochromatin. In humans, the phenomenon of position effect may also involve disturbing the usual chromatin environment of a gene, reflecting the heterogeneity of the human genome in terms of chromatin structure and transcriptional permissiveness.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:649096 |
| Date | January 1996 |
| Creators | Danes, Sarah |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/13557 |
Page generated in 0.0024 seconds