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

Abstract

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder with multisystemic manifestations caused by heterozygosity for a partial deletion of chromosome band 7q11.23. The breakpoints cluster within regions located approximately 1 cM either side of the elastin (ELN) locus. We have characterized a duplicated region near the common deletion breakpoints, which includes a transcribed gene. The centromeric (C) and telomeric (T) copies are almost identical in the duplicated 3[prime] portions but diverge at their 5[prime]-ends. C-specific 4.3 kb mRNA and T-specific 5.4 kb mRNA are widely expressed in embryonic and adult tissues. The telomeric gene gives rise to several alternatively spliced forms and is deleted in all WBS individuals who have documented ELN deletions. Database searches revealed that this gene encodes BAP-135, a protein phosphorylated by Bruton's tyrosine kinase in B cells, as well as the multifunctional transcription factor TFII-I, hence the gene name GTF2I. The centromeric gene is not deleted in WBS and appears to be a partially truncated 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 recognizes a>3 Mb Not I junction fragment that is unique to individuals with 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 chromosome 7 homologs and/or to intrachromosomal rearrangements. Hemizygosity for GTF2I may also contribute to the WBS phenotype.

Signal-induced functions of the transcription factor TFII-I

“…The most conserved region within these repeats is called the I-repeat (23). There are four characterized alternatively spliced isoforms of TFII-I: Δ (957 amino acids), α (977 amino acids), β (978 amino acids) and γ (998 amino acids) (26,27). Of the four, the γ-isoform is most likely expressed predominantly in neuronal cells and the α-isoform is lacking in murine cells (26).…”

“…There are four characterized alternatively spliced isoforms of TFII-I: Δ (957 amino acids), α (977 amino acids), β (978 amino acids) and γ (998 amino acids) (26,27). Of the four, the γ-isoform is most likely expressed predominantly in neuronal cells and the α-isoform is lacking in murine cells (26). Each isoform contains all the repeats, the basic region (BR, also the DNA binding domain), a putative leucine zipper (LZ) and a functional nuclear localization signal (amino acids 297-304 with respect to the Δ-isoform) (27,28) (Figure 1A).…”

“…WBS is a neuro-developmental disorder with multisystem manifestations, including supravalvular aortic stenosis (SVAS), hypercalcemia in infancy. These patients also exhibit mild to moderate mental retardation, cognitive defects and characteristic craniofacial features (26,63). The frequency of this genetic haploinsuffiency is estimated to be 1 in 20,000 live births.…”

“…Although most cases are sporadic, WBS is inherited as an autosomal dominant trait in a select few families. To date, 17 open reading frames have been identified within this region (26,63). Despite the fact that WBS is a multisystem dysfunction most likely caused as a result of haplo-insufficiency in several genes, it is anticipated that there will be a strong genotype-phenotype correlation.…”

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

“…The high conservation (99.9%) of the coding sequences of GTF2I and GTF2IPI, as well as the preservation of restriction fragment patterns at both loci, indicate that the duplication is of recent evolutionary origin. 5 With probes containing parts of the elastin gene the deletion can be readily detected by fluorescence in situ hybridisation (FISH) in 90 ± 99% of individuals with WBS. 6 ± 11 It has been postulated that a number of 7q11.23 deletions occur in association with an interchromosomal rearrangement, indicative of an unequal crossing-over event between mispaired repeats of the two homologous chromosomes 7.…”