CONSTRUCTION AND ANALYSIS OF A SEQUENCE-READY MAP IN 4Q25 - RIEGER SYNDROME CAN BE CAUSED BY HAPLOINSUFFICIENCY OF RIEG, BUT ALSO BY CHROMOSOME BREAKS APPROXIMATE-TO-90 KB UPSTREAM OF THIS GENE

The autosomal dominant disorder Rieger syndrome (RIEG) shows genetic h eterogeneity and has a phenotype characterized by malformations of the anterior segment of the eye, failure of the periumbilical skin to inv olute, and dental hypoplasia. The main locus for RIEG was mapped to th e 4q25-q27 chromosomal segment using a series of cytogenetic abnormali ties as well as by genetic linkage to DNA markers, Recently, a bicoid- related homeobox transcription factor gene called RIEG has been cloned , characterized, and proven to cause the 4q25 linked RIEG. Its mode of action in the pathogenesis of RIEG was not conclusively proven, since most etiological mutations detected in the RIEG sequence caused amino acid substitutions or splice changes in the homeodomain. Through FISH analysis of a 460-kb sequence-ready map (PAC contig) around RIEG that we report in this paper, we demonstrate that the 4q25 linked RIEG dis order can arise from the haploid, whole-gene deletion of RIEG, but als o from a translocation break 90 kb upstream from the gene. The data pr ovide conclusive evidence that physical or functional haploinsufficien cy of RIEG is the pathogenic mechanism for Rieger syndrome. The map al so defines restriction fragments bearing sequences with a potential ke y regulatory role in the control of homeobox gene expression. (C) 1998 Academic Press.