A DUPLICATED GENE IN THE BREAKPOINT REGIONS OF THE 7Q11.23 WILLIAMS-BEUREN-SYNDROME DELETION ENCODES THE INITIATOR BINDING-PROTEIN TFII-I AND BAP-135, A PHOSPHORYLATION TARGET OF BTK

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder with m ultisystemic manifestations caused by heterozygosity for a partial del etion of chromosome band 7q11.23. The breakpoints cluster within regio ns located similar to 1 cM either side of the elastin (ELN) locus, We have characterized a duplicated region near the common deletion breakp oints, which includes a transcribed gene. The centromeric (C) and telo meric (T) copies are almost identical in the duplicated 3' portions bu t diverge at their 5'-ends. C-specific 4.3 kb mRNA and T-specific 5.4 kb mRNA are widely expressed in embryonic and adult tissues, The telom eric gene gives rise to several alternatively spliced forms and is del eted in all WBS individuals who have documented ELN deletions. Databas e searches revealed that this gene encodes BAP-135, a protein phosphor ylated by Bruton's tyrosine kinase in B cells, as well as the multifun ctional transcription factor TFII-I, hence the gene name GTF2I. The ce ntromeric gene is not deleted in WBS and appears to be a partially tru ncated expressed pseudogene with no protein product (gene name GTF2IP1 ). Both loci map to different genomic clone contigs that also contain other deleted and non-deleted loci, A probe from the shared region rec ognizes a>3 Mb Notl junction fragment that is unique to individuals wi th the WBS deletion. Therefore, the duplicated region containing GTF2I and GTF2IP1 respectively is located close to the deletion breakpoints and may predispose to unequal meiotic recombination between chromosom e 7 homologs and/or to intrachromosomal rearrangements, Hemizygosity f or GTF2I may also contribute to the WBS phenotype.