Aniridia is a panocular human eye malformation caused by heterozygous null
mutations within PAX6, a paired-box transcription factor, or cytogenetic de
letions of chromosome 11p13 that encompass PAX6. Chromosomal rearrangements
also have been described that disrupt 11p13 but spare the PAX6 transcripti
on unit in two families with aniridia. These presumably cause a loss of gen
e expression, by removing positive cis regulatory elements or juxtaposing n
egative DNA sequences. We report two submicroscopic de novo deletions of 11
p13 that cause aniridia but are located >11 kb from the 3' end of PAX6. The
clinical manifestations are indistinguishable from cases with chain-termin
ating mutations in the coding region. Using human x mouse retinoblastoma so
matic cell hybrids, we show that PAX6 is transcribed only from the normal a
llele but not from the deleted chromosome 11 homolog. Our findings suggest
that remote 3' regulatory elements are required for initiation of PAX6 expr
ession.