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3' deletions cause aniridia by preventing PAX6 gene expression
J D Lauderdale1, J S Wilensky, E R Oliver
1Departments of Internal Medicine and Human Genetics, University of Michigan, 4510 MSRB I, Box 0650, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0650, USA.
Summary
Aniridia, a severe eye malformation, can result from deletions affecting the PAX6 gene. These deletions, even when distant from the gene, disrupt PAX6 expression, indicating the importance of remote regulatory elements.
Area of Science:
- Genetics
- Developmental Biology
- Ophthalmology
Background:
- Aniridia is a congenital eye malformation linked to PAX6 gene mutations or deletions.
- Previous studies identified chromosomal rearrangements disrupting 11p13, causing aniridia by affecting PAX6 expression.
- The precise regulatory mechanisms controlling PAX6 expression remain incompletely understood.
Purpose of the Study:
- To investigate the role of regulatory elements outside the PAX6 transcription unit in aniridia.
- To characterize novel deletions causing aniridia and their impact on PAX6 gene expression.
- To elucidate the genetic basis of aniridia in families with chromosomal abnormalities.
Main Methods:
- Analysis of submicroscopic de novo deletions in patients with aniridia.
- Utilizing human x mouse retinoblastoma somatic cell hybrids for gene expression studies.
- Comparative genomic hybridization and fluorescence in situ hybridization (FISH) for deletion mapping.
Main Results:
- Identified two de novo deletions of 11p13, located >11 kb from the 3' end of PAX6, causing aniridia.
- Clinical phenotypes were consistent with coding region mutations in PAX6.
- Somatic cell hybrid studies demonstrated that PAX6 was not transcribed from the deleted chromosome 11 homolog.
Conclusions:
- Remote 3' regulatory elements are crucial for the initiation of PAX6 expression.
- Disruption of these distant regulatory regions can lead to aniridia.
- This finding expands the understanding of genetic mechanisms underlying aniridia and PAX6 regulation.